DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE
Carolyn M. Kercsmar, M.D.
Fernando D. Martinez, M.D.
Theodore F. Reiss, M.D. (Industry Rep)
Michael Schatz M.D., M.S.
Karen S. Schell, RRT, (Consumer Rep)
Erik R. Swenson, M.D.
SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (VOTING)
T. Prescott Atkinson, M.D., Ph.D.
I. Marc Moss, M.D.
C O N T E N T S
Call to Order and Opening Remarks:
Conflict of Interest Statement:
Robert Meyer, M.D. 10
History of the
Eugene Sullivan, M.D. 40
Randall Lutter, Ph.D. 60
Questions from the Committee to the Speakers 76
Open Public Hearing (1)
Pamela Wexler, U.S. Stakeholders Group 93
Elaine Jones, Ph.D. GlaxoSmithKline 104
Ron Garutti, M.D., Schering-Plough 119
Open Public Hearing (2)
Ballard Jamieson, Jr., International 143
Pharmaceutical Aerosol Consortium
Neil Flanzraich, IVAX Corporation 149
Richard Rozek, Ph.D., National Economic 162
David Doniger, Natural Resources 172
Joseph Rau, M.D., American Association 181
for Respiratory Care
Jodi Finder, Asthma Therapy Coalition 183
Steven Bernhardt, M.D., 190
C O N T E N T S (Continued)
Open Public Hearing (2) (Continued)
Nancy Sander, Allergy and Asthma Network 193
Mothers of Asthmatics
Anthony Marinelli, M.D., American 198
Ira Finegold, M.D.,
Asthma and Immunology
Spenser Atwater, M.D., Joint Council on 207
Allergy, Asthma and Immunology
(statement read by Ms. Jain)
Committee Discussion 211
P R O C E E D I N G S
Call to Order and Opening Remarks
DR. CHINCHILLI: Good morning, everyone.
This is a meeting of the Pulmonary-Allergy Drugs
Advisory Committee. We are here today to discuss
whether the use of chorofluorocarbons as
propellants in albuterol-metered dose inhalers in
no longer an essential use under the criteria as
set forth in the Code of Federal Regulations 12 CFR
My name is Vern Chinchilli. I am the
Acting Chair today for the committee. So we will
have some opening remarks. The first thing I
usually do is introduce--I will ask each committee
member--we will go around the table--to introduce
themselves. Please make sure you hit the
microphone button so it is on.
Why don't we start with Dr. Reiss. Oh; he
is not here? Dr. Atkinson?
DR. ATKINSON: I am
Allergy and Immunology at
DR. SCHELL: Karen Schell, Consumer
DR. MARTINEZ: I am Fernando Martinez from
DR. SCHATZ: I am Michael Schatz, Allergy
and Immunology, Kaiser
DR. KERCSMAR: Carolyn Kercsmar, pediatric
pulmonology, Rainbow Babies and Children's Hospital
DR. MOSS: Mark Moss, Pulmonary and
DR. CHINCHILLI: Vern Chinchilli. I am a
biostatistician from the Penn State Hershey Medical
MS. JAIN: Shalini Jain, Exec Sec, Acting,
and, at this point, for this meeting for the
Pulmonary-Allergy Drugs Advisory Committee.
DR. SWENSON: Erik Swenson, Pulmonary and
Critical Care Medicine at the University of
Washington in Seattle.
DR. LUTTER: Randy Lutter, Economics, with
the Office of the Commissioner in FDA.
DR. MITCHELL: Wayne Mitchell, Office of
Regulatory Policy in the Center for Drug Evaluation
and Research. I am the draftsman on the rule.
DR. SULLIVAN: I am Gene Sullivan. I am
the Deputy Director of the Division of Pulmonary
and Allergy Drug Products at FDA.
DR. MEYER: I am Bob Meyer. I am the
Director of the Office of Drug Evaluation II in the
Center for Drugs at FDA.
DR. CHINCHILLI: Thank you, everyone, for
Next, Shalini Jain will talk about the
Conflict of Interest Statement.
Conflict of Interest Statement
MS. JAIN: The following statement
addresses the issue of conflict of interest with
respect to this meeting and is made part of the
record to preclude even the appearance of such at
Based on the agenda, it has
determined that the topics of today's meeting are
issues of broad applicability and there are no
products being approved at this meeting. Unlike
issues before a committee in which a particular
product is discussed, issues of broader
applicability involve many industrial sponsors and
academic institutions. All special government
employees have been screened for their financial
interests as they may apply to the general topic at
Because there has been reported interest
in pharmaceutical companies, the Food and Drug
Administration has granted general-matters waivers
to the special government employees who require a
waiver under Title 18, United States Code Section
208 which permits them to participate in today's
A copy of the waiver statement may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
of the Parklawn Building. Because general topics
impact so many entities, it is not
recite all potential conflicts of interest as they
apply to each member, consultant and guest speaker.
FDA acknowledges that there may be
potential conflicts of interest but, because of the
general nature of the discussion before the
committee, the potential conflicts are mitigated.
With respect to FDA's invited industry
representative, we would like to disclose that Dr.
Theodore Reiss is participating in this meeting as
an industry representative acting on behalf of
regulated industry. Dr. Reiss is employed by
In the event that the discussion involves
any other products or firms not already on the
agenda for which an FDA participant has a financial
interest, the participants are aware of the need to
exclude themselves from such involvement and their
exclusion will be noted for the record.
With respect to all other participants, we
ask, in the interest of fairness, that they address
any current or previous financial involvement with
any firm whose products they may wish to
DR. CHINCHILLI: Thank you, Ms. Jain.
We are ready to start the regular part of
the agenda. Dr. Meyer, the Director of the Office
of Drug Evaluation II, will have some opening
DR. MEYER: Good morning. Although I
service Director of the Office of Drug Evaluation
II in the Center for Drugs, I, for many years,
served for the Center Lead on issues related to the
Montreal protocol and phase-out of CFCs from
FDA-regulated medical products, specifically MDIs
for asthma and COPD.
So, on behalf of the FDA, I wish to
welcome all the participants in today's meeting of
the Pulmonary and Allergy Drugs Advisory Committee.
I want to thank you in advance for your time and
your efforts and your thoughtfulness in your
discussions and advice.
When we were originally
meeting, we had hoped the meeting would coincide
with the open public comment period of a proposed
rule to delist albuterol as an essential use of
ozone-depleting substances, specifically CFCs.
This is now, indeed, the case although the rule
just went on display at the Federal Register and,
subsequently, on our web page yesterday afternoon.
I believe you have been provided copies.
I would point out that, although the
proposed rule is posted on these sites, it is not
officially published until June 16 so what you have
in hand is a pre-publication version that means
some dates are missing and the pagination will
change when it is officially published in the
I would also point out that the six-day
comment period starts on the day of official
publication which will be June 16 although,
clearly, the discussions today will be considered
as part of the docket for us to consider in coming
to the final rule.
We particularly look foreword
input from the public in our public hearing portion
of the meeting and I thank those individuals and
organizations who are presenting or have otherwise
submitted materials for the record.
All of the presentations, submissions and
the deliberations of the committee and advice given
today will be entered into the docket, as I said,
and will help us to move forward towards finalizing
this rule with a target of Summer of 2005.
I would note to the committee that we are
not seeking any formal votes today on a particular
question but do, very much, seek your counsel on
the matter at hand whether the use of CFCs in
albuterol metered-dose inhalers remains an
essential use under the provisions of our
We will have three speakers from the FDA
today. I will first speak, giving a history of the
Montreal Protocol and FDA's regulations regarding
essential use of CFCs. Dr. Eugene Sullivan, from
the Division of Pulmonary and Allergy Drug
Products, will then follow with
related to the current situation with albuterol and
its essentiality as well as some related issues.
To close FDA's presentations, Randy
Lutter, who is FDA's Chief Economist in the Office
of Planning, will speak on economic considerations
related to the potential for delisting albuterol as
an essential use.
Again, we would like to thank you for your
time in being here and look forward to today's
DR. CHINCHILLI: Thank you, Dr. Meyer.
I believe you are on the agenda next for
History of the Montreal Protocol and 21 CFR 1.125
DR. MEYER: Good morning, again, from this
venue. When I arrived at the agency about ten
years ago this July, I can assure you that I never
envisioned I would be standing here representing
the FDA on the issue of ozone protections. As a
pulmonologist, it was not something that entered my
mind at that point.
But life is full of happy
This picture on my title slide is from NASA's web
page and shows the largest recorded ozone hole over
the Antarctic which actually was shot last
September of 2003. This serves as a fitting
graphic to start a talk on the history of the
Montreal Protocol as well as the FDA regulations
that related to chlorofluorocarbons and
The stratosphere is a region of the
earth's atmosphere that begins roughly ten to
fifteen kilometers above the earth's surface,
depending on the particular part of the earth one
is focused on, and extends up to 50 kilometers.
Most of the ozone, over 90 percent of the ozone, in
the atmosphere is in this stratosphere where it
acts, in part, to filter ultraviolet B radiation by
absorbing this band of wave length from sunlight.
Increases in UV-B reaching the earth's
surface are detrimental to human health in a number
of ways as well as to other life forms and to
synthetic materials. The human consequences of
most note are increases in skin cancer as
cataracts and alterations in immunity. Those skin
cancers are both of the melanoma type as well as
This, then, is the background as to why
there is a worry about protecting the ozone layer.
Also, by way of background, since we are talking
about regulations, I would like to explain how
rules are made. The FDA operates under laws or
statutes, most notably the Food, Drug and Cosmetic
Act, as well as other statutes.
However, no matter how well written or
detailed a law may be, it cannot provide sufficient
detail to inform the specific process of
regulation. This is accomplished by the writing of
rules which, when finalized, have the force of law
behind them as it represents the agency's
implementation of the respective law that we are
The usual pathway for reaching a final
regulation or rule is by what is called Notice and
Comment Rulemaking. Formally, that involves the
FDA publishing a Notice of Proposed
NPR, in the Federal Register such as will shortly
occur for albuterol.
An NPR typically has a comment period
between 60 and 90 days--again, that, for the rule
at hand is 60 days beginning on June 16--during
which time comments from the public, including the
regulated industry, are solicited. These comments
are then individually considered and addressed in
reaching a final rule. Rulemaking is an integral
part of the CFC non-essentiality determinations. I
will speak more on this later.
The purpose of my talk, then, this
morning, is to give a history and background of the
Montreal Protocol and to FDA's regulations with
regard to ozone protection. The timeframes for
these, as they developed, overlap and, obviously,
the efforts intersect. So I will interweave the
two topics in my talk.
Back in the mid-1970s, two scientists
operating out of trial University of California at
Irvine posited that chlorofluorocarbons were
reaching the stratosphere were UV
would cleave off the chloride atoms that, in turn,
catalyze the destruction of ozone. This work was
by Molina and Rowland, who later was awarded the
At the time that this article came out,
chlorofluorocarbons, or CFCs, were ubiquitous in
use in multiple applications. They became
widespread for a number of reasons. Amongst these
were that CFCs are quite non-toxic which,
parenthetically, makes them excellent for use in
inhalers, very stable and had physical-chemical
properties that were advantageous for use in
refrigerant systems, air conditioners and aerosols.
The stability of these gasses is, in part,
why they are so devastating to the stratosphere.
They have a very long half-life when they reach the
stratosphere and, therefore, damage the ozone layer
for many, many years.
In 1978, really in a fairly remarkably
short time after the seminal publication by Rowland
and Molina, the U.S. Government acted to address
the issue of CFCs and to place a general
ban on the
use of CFCs as propellants in consumer aerosol
products. This was accompanied by a rule from FDA
in the relevant chapter of the Code of Federal
Regulations or what we call the CFR, and that, for
the FDA, is the 21st Chapter, banning the use of
CFCs in all regulate products except for those
deemed as essential uses.
This rule is now called 2.125 because that
is the citation where it is published. That is how
we will be referring to it throughout much of the
day. Notably exempt at that time were broad
classes of asthma and allergy products such as a
nasal steroids, the inhaled steroids, and
In 1987, as the science of ozone depletion
advanced and as there was further evidence
accumulated about ozone reductions, a global treaty
known as the Montreal Protocol on substances that
deplete the ozone layer was initiated. At that
time, 27 nations, including the USA, were
I would note, just to make this
sort of current events, that this was during the
latter years of the Reagan Administration. The
original protocol now has at least 184 signatory
countries. As of the time that I queried the web
page for the Secretariat of the Ozone Efforts about
a month, it was 184 countries. Countries are also
called parties under the terms of the protocol.
This is widely considered a successful
example of global, environmental cooperation.
Indeed, there is evidence that the chloride levels
in the stratosphere have stabilized in recent years
and it is expected that the stratospheric ozone
layer will slowly recover to levels that were seen
in the early 1980s by the middle part of this
The original phase-out of CFCs was slated
for the Year 2000. That was taken in London in
1990. This was moved up, however, by meeting of
the parties in Copenhagen which occurred in 1992.
It was moved up to 1995, at the end of '95, because
of increasing evidence of marked ozone depletion,
particularly over the extreme southern
as you saw in my first slide.
This phenomenon is commonly called an
ozone hole. It is not really a true hole but an
area of extreme depletion. I should point out
that, although it is a depletion that is
particularly prominent over the southern
hemisphere, it has occurred globally.
I should also point out that, while we are
focussing on CFCs today because that is the
relevant topic for the FDA, the protocol, itself,
has controls on many other ozone-depleting
substances such as halons, HCFCs, methylbromide,
carbon tetrachloride and other substances.
So, while the CFCs are an important issue
to FDA and, indeed, to the Montreal Protocol, I do
want to be clear that the protocol is a much
broader effort in scope than simply the
In accordance with the Copenhagen
Amendment to the protocol, the production and
importation of CFCs became illegal in economically
developed countries including the United
of January 1, 1996. The rest of the world is
expected to have phased out new CFCs by 2010.
Metered-dose inhalers, or MDIs, for asthma and COPD
are currently considered as potentially acceptable
essential uses of CFCs. I say potentially
acceptable because there is a nomination process
that parties undergo if they want to produce or
import CFCs for use in MDIs.
These nominations have to be done annually
and the process generally begins nearly two years
prior to the year in question. So, for instance,
the U.S. had to submit its nomination for 2006 in
I would also point out that nominations
are historically approved by consensus of the
parties to the Montreal Protocol but, actually, if
the consensus process fails, there is a mechanism
within the protocol to default to a two-thirds
I wanted to go through sort of how the
protocol has evolved over time This is a decision
of the parties from the Copenhagen
Decision IV, or this IV, means that it was from the
fourth meeting of the parties and it was the 25th
decision taken at that meeting. This was the
definition at the time that they decided the
phase-out would begin on January 1, 1996, or the
ban on CFCs, that stated that, "All essential uses
of CFCs would have to be based on products being
necessary for public health and that there were not
adequate alternatives." The failure to have
adequate alternatives could either be based on
technical problems or economical problems.
But this was macroscopic in terms of both
this determination as well as the general use. In
other words, it was widely accepted at that point
in general that the uses of CFCs and MDIs for
asthma and COPD could be considered an essential
However, over time, the protocol evolved
so that, as the phase-out progressed, as
alternatives became available, this sort of more
generally and broad interpretation of what was an
essential use became narrower and
In Beijing, at the twelve meeting of the
parties in the Year 2000, another decision was
taken that said that any product approved after
December, 2000, must individually meet these
criteria for essentiality under Decision IV-25.
So, in other words, it is not just a general
consensus any longer that the use of CFCs for
asthma and COPD was acceptable but, in this case,
any new product would have to individually meet
So this was a product-centered
determination of essentiality that essentially
precluded new CFC generics and, actually, many
other new CFC products. It essentially was
shutting the door, for all intents and purposes,
except under extraordinary circumstances for any
new CFC MDIs.
This past year, in Nairobi, a further
decision was taken by the parties that became even
more narrow and specific in scope. It stated that
essential-use nominations from parties
the past, had been lumped and general and not
parsed out for the purposes of the protocol's
evaluation, or the Montreal Protocol evaluation.
Now it stated that essential-use
nominations have to be specific; for example, a
country might say they need some
undetermined--well, they would have to give a
specific number, but some number of tons for
albuterol. No quantity of essential-use CFCs would
be authorized for albuterol. This is, I think,
particularly germane today--that no quantity of
essential uses of CFCs would be authorized,
period--actually, this is a little bit of a
misstatement in the way this is terms--if a country
does not submit to the meetings of the
party--beginning of the open-ended working group,
excuse me, in the summer of 2005--a clear plan for
when albuterol, specifically, would no longer be
Let me go through that again, because this
is key. Countries who request essential uses,
including the United States, will have to
the Ozone Secretariat of the Open-Ended Working
Group in the summer of 2005 a plan or a
date-certain for when albuterol will no longer be
considered essential. If parties fail to do that,
including the U.S., we will not receive and
essential-use allocation at all.
Now, turning a little bit from the
evolution of the Montreal Protocol back to our
rules and regulations, the Clean Air Act Amendments
of 1990 codified the Montreal Protocol into U.S.
law. The implementing EPA regulations specifically
call for FDA to define what is an essential medical
use and refers to our 2.125 as the source of the
listing of those essential products.
I remind you, however, that 1.125 was
finalized before the Montreal Protocol existed and
before the Clean Air Act Amendments.
The rule, as promulgated in 1978, stated
that a CFC-containing product regulated by FDA was
misbranded or adulterated under the FD&C Act; that
is, it would be illegal under our authority unless
deemed essential and listed in
definition of essential was that there would be no
technically feasible alternatives; that the use of
CFCs in that particular product provided
substantial health, public or environmental
benefit; and that the release of the CFC was small
or justified given the public-health benefit.
Notably, the FDA rule had no mechanism to
determine when things were no longer essential and,
therefore, to delist them. It did have ways to add
new classes of drugs to the list and, in fact, that
was done over the years. But it had no specified
way for delisting things.
Another important feature of the rule that
needed to be correct is that many drugs, including
albuterol, were not specifically mentioned as
essential uses but, rather, there were broad
definitions of drug classes, if you will, such as
albuterol and other beta-agonists being under the
general term of adrenergic bronchodilators for
So, realizing that we needed to correct
some things about this rule that was
to the Montreal Protocol and the Clean Air Act, and
specifically to develop a mechanism for delisting
things that were no longer essential, FDA, in 1996,
undertook revisions. Because of wanting to do
these revisions in the very most public and
informed manner, the FDA took an additional step to
the steps that I gave you earlier for the
publication of a rule, doing something called an
Advance Notice of Proposed Rulemaking which,
actually, starts with another cycle of notice and
This effort proved very successful if
measured by the number of comments. We got close
to 10,000 comments to this Advance Notice of
Proposed Rulemaking, many of which, I would point
out, were actually patient-based comments sparked
by lobbying efforts.
We then took all 10,000 comments and
reviewed them and responded to them. I would note
that there were many fewer substantive comments but
still all of the comments were carefully reviewed
and considered. That resulted in the publication
of a Notice of Proposed Rulemaking in 1999.
That proved to be less controversial in
many ways and it received many fewer substantive
comments and comments overall and, as I said, had
seemingly much less controversy. So FDA moved
forward with amending 2.125 in July of 2002 and
this went into effect six months later.
The 2002 revisions did a number of things.
First of all, it listed essential uses as
individual moieties. I would point out that, to
coincide more correctly with the Montreal Protocol,
it no longer referred simply to chlorofluorocarbons
but to ozone-depleting substances. But, for the
purposes of today and for all intents and purposes,
most of FDA's activities, you can consider ODS, or
ozone-depleting substances, as being synonymous
with CFCs in terms of this discussion.
So, for instance, albuterol is now
separately listed rather than there just being a
broad class without any citation of individual
The revisions also added a
for investigational new drugs to be developed with
CFCs and it raised the bar for new listings of
essential uses as well. There was also a list of
criteria, importantly for today, for determining
when individual uses were no longer considered
One other revision I would point out that
is not on this slide was that we shifted the rule,
because of the re-write of the Clean Air Act, to
state that if something was no longer essential, it
would be considered illegal to market it under the
Clean Air Act and not under the Food, Drug and
Let me go through these important
nonessentiality criteria. I would point out that
Dr. Sullivan will revisit these in his talk
specific to albuterol, but I think they are worth
hearing a couple of times.
For a specific moiety to be considered
nonessential, there would have to be at least one
non-ozone-depleting-substance product--in other
words, a non-CFC product--with that same
moiety, and here I am only talking about a moiety
where there is only one marketed-brand product or
one marketing strength, so, at least one active
moiety with the same indications, same route of
administration--in other words, oral albuterol
would not be considered an alternative under these
criteria--and about the same level of convenience.
We stated in the preamble to the final
rule that, although dry-powdered inhalers might fit
this description, we felt that MDIs would most
neatly do so and, I think, most logically do so.
In addition to this, these alternatives
would have to have adequate postmarketing data to
prove that they are not only safe and effective for
approval purposes but will serve as an adequate
alternative in the marketplace. Importantly, there
would have to be production capabilities and
supplies that are adequate to meet the needs of
patients who depend on the use of this moiety for
the treatment of their asthma or COPD and patients
who require the CFC product are adequately served.
I would state, and I am sure
will bring this up as well, that, under the
considerations for adequately served, is the issue
of price in that--not so much whether there will be
any impact on the price to the patients but will
patients be disaffected or unable to get the
medicine if there is a price differential.
We didn't build that in as an explicit
consideration, the cost issue, but it was mentioned
in the preamble because many of the comments to the
ANPR and to the PR as we developed this re-write of
2.125, brought up the issue of affordability.
Now, specific to albuterol which
has--actually, this should say one branded product
available and three generics marketed--for moieties
with more than one available product or strength
such as albuterol, you would need at least two
non-ozone-depleting-substance products with the
same active moiety, the same indication, route of
administration, about the same level of
convenience, and the other criteria were the same.
So, in other words, if the moiety was
represented in the marketplace by
strengths or different numbers of products from
different manufacturers, we felt it important that
there be sort of at least--if not a full match to
the range, at least alternatives that represented
Let me just show you, to wrap up this
background, where all this has led over time. This
is a graph of the global situation for CFC
essential uses. Let me go through the two lines
here. This is 1996. The open space is actually
the year, not the hatch mark, so we go from 1996
out to 2006 on the X axis. On the Y axis, we are
talking about metric tons. A metric ton is 2200
pounds, so these are metric tons of total CFC used
for essential-use allowances in these developed
The red line is the amount that was
exempted--in other words, the amount that was
nominated and approved by the parties. The blue
line is the amount that was actually used over
time. The green line is the stockpiles. So these
are the amounts held by the countries
represent new production.
You can see that the peak of the use
worldwide, or at least in these developed countries
that were putting in essential uses, was just about
9,000 metric tons occurring in the 1997-1998 range.
This has fallen by 2003 down to just a little bit
over 4,000 tons. One would project from the amount
nominated, which generally has been historically
higher than the amounts actually used, that this
will further fall in the coming two years rather
dramatically. So the amounts nominated in 2006 are
down below 3,000 metric tons.
I apologize for this being a little harder
to see. I could not manipulate this as easily as
the last one. But this is the situation for the
United States, itself. Again, this is metric tons
per year on the Y axis, years on the X axis. I
know that will be very difficult for people in the
audience to see but the main point here is this is
the blue line, which is the amount used for
metered-dose inhalers in the United States.
You can see, for the most part,
has been reasonable stable from the
pre-Montreal-Protocol years through the time period
of the Montreal Protocol, although there was a
rather substantial fall in the last couple of
years--this goes out to 2002--at which time the
total use was just a little bit over 1500 metric
tons in the United States. I would point out that
the use for albuterol is a substantial portion of
the United States nomination.
Let me also now talk about the transition
within the United States, itself. What we have
here is a slide that attempts to display the
original listings under the 2.125 and then the
specific listings under 2.125, and then to display
changes over time.
So, originally, 2.125 had the broad class
of beta-adrenergic agents: inhaled corticosteroids;
nasal steroids; the cromones--cromolyn and
nedocromil were actually separately listed;
ipratropium; atropine, which was actually approved
for use in Desert Storm; a combination product,
albuterol and ipratropium.
I think it is important for me to point
out, if Dr. Sullivan does not and if it is
repeated, I think it is still and important thing;
we are not talking about a combination product
today. We are only talking about those products
that solely contain albuterol as their active
ingredient; and then a number of other products,
many of which were actually, as you can see, not
MDIs. So we had talc, contraceptive foams, rectal
foams, ergotamine MDIs, polymxin, anesthetic drugs
including those that directly use CFCs, and
When the re-write of 2.125 was finalized
in 2002, those products listed in red were taken
out, many of these because they either did not meet
the criteria any longer or were not considered
essential under the Montreal Protocol, or they were
no longer marketed.
So, at the time of the finalization,
isoetharine, isoproterenol, the nasal steroids as a
class, contraceptive foams, rectal foams, polymyxin
and nitroglycerine all came out and were
separately listed in 2.125.
The products in yellow could be considered
as potential for delisting soon, these because they
are no longer available, marketed as CFC products.
One of the things in 2.125 re-write that was said
was that, if a product was not marketed for a
substantial period of time, one could consider it
to be not essential. Those would include
bitolterol, salmeterol, which was discontinued by
the manufacturer, dexamethasone, talc, ergotamine
MDIs and anesthetic drugs.
Beclomethasone is no longer marketed, the
MDIs, at least not newly produced MDIs, and there
are alternatives. So that is another potential
delisting. Albuterol, I guess I did not put in
yellow here because that is what we are here to
discuss today is whether that has met the criteria
that we laid out in the revisions of 2.125.
So, to conclude my talk, the U.S.
Government moved proactively to address the issue
of ozone depletion shortly after the development of
ozone science, and the U.S. Government had a
key role in the formation and the conduct of the
Montreal Protocol. The Montreal Protocol is
considered a successful treaty that has led to
important reductions in CFCs and other
ozone-depleting substances and, as I mentioned,
there are data to suggest that the recovery of the
stratospheric ozone layer is in the early stages.
Now, the Montreal Protocol, as I pointed
out from the evolution of some of the decisions
taken, is increasingly moving towards control in
its specific essential uses, notable amongst those
would be albuterol.
Just as a transition slide, I chose
another picture off the NASA web page of the ozone
depletion. Remember that I said we would recover
to the early '80's levels by the mid part of this
century. This shows the Antarctic region in 1983
and the Antarctic region in 1993. You can see the
difference where the white is the thicker ozone.
You can see the difference in the ozone layer in
So, thank you very much.
DR. CHINCHILLI: Thank you, Dr. Meyer.
You finished a few minutes early so let's
see if there are any questions from our committee
members. I have one, Dr. Meyer. What was the
rationale behind the decision about not pursuing
this with the--not considering the dry-powdered
inhalers as a similar moiety?
DR. MEYER: What we said was that we
thought they could serve as an alternative but it
would not be as automatic as an MDI. So, in fact,
I think if there were an albuterol dry-powdered
inhaler that met those criteria otherwise, we would
I think, at the time we were writing it,
we had considerations such as, at that point,
albuterol was available in a capsule, an individual
capsule, rotohaler-type device where one would
place it in, turn it and breathe. We did not feel
that that had sort of the same level of convenience
and portability and so on as an MDI. So I think we
wanted to not exclude all dry-powdered inhalers out
of hand but say that they would have to
certain levels of convenience and patient
Again, the presumption in the preamble to
rule was that the MDIs would most neatly do that
because they are very much similar.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: Dr. Meyer, in your
multicolored slide, there was some products in
white. I presume those will continue to be
available by way of CFCs and includes epinephrine,
for example; is that correct?
DR. MEYER: Some of those products in
white are, in fact, under development in that are
alternatives being developed. Some are not. One
of the provisions in the rule that I didn't bring
up today because it wasn't fully germane but I
would be happy to answer as a part of your question
is the fact that, beginning next year, we will have
the ability to call this body into meetings, have
the advisory committee come to meetings, to discuss
those products that remain on the list that are not
being reformulated and whether they
I think, just parenthetically, epinephrine
will be something that will be important for us to
discuss at some time in the future.
DR. CHINCHILLI: Any other questions from
the committee? If not, thank you, again, Dr.
I guess we will move forward with Dr.
Sullivan, the Deputy Director of the Division of
Pulmonary Drug Products.
DR. SULLIVAN: Good morning. I am Gene
Sullivan. I am a pulmonologist. I am also the
Deputy Director of the Division of Pulmonary and
Allergy Drug Products at FDA. For the next twenty
or thirty minutes, I am going to be discussing some
of the medical considerations in regard to this
proposal to remove albuterol from the list of drug
substances that are considered essential uses for
Following my talk, you will hear from Dr.
Lutter, as Dr. Meyer mentioned. Dr. Lutter will go
into more depth in regard to the economic aspects
of this question. Then, following that, you will
hear some very important information from
interested parties who will be speaking during the
open public hearing.
So this slide provides a background
overview of my talk. Dr. Meyer has just given a
very nice background on the overarching issues
about the Montreal Protocol and the FDA Regulation
2.125, so my background remarks will be brief.
Then, also, briefly, I will review the currently
marketed albuterol MDI products. But the bulk of
my talk will be in this section specifically
looking at the criteria that Dr. Meyer mentioned
that are included in the Amended 2.125, so the
currently existing regulation, and specifically
examining those criteria in regard to how they
apply in the case of albuterol.
Then, finally, I will touch on a couple of
other issues which, although they are not directly
responsive to the criteria laid out in 2.125, I
think are clearly important issues to
deciding on a path forward with regard to
So, again, Dr. Meyer has provided very
nice background on the Montreal Protocol and on the
FDA regulation concerning the essential-use
determinations, that being 21 CFR 2.125 and, as Dr.
Meyer mentioned, I will be referring to it as 2.125
from now on.
As you know, the agency is currently
considering whether albuterol, in fact, has met the
criteria that are listed in 2.125 for removal from
the list of essential uses. This process that we
are embarking on is in keeping with the goals of
the Montreal Protocol, specifically, the goal of
phasing out production and importation of
ozone-depleting substances including
I think the step forward with albuterol is
an important step in that direction particularly
because approximately half of the annual
essential-use CFC allocation in the U.S. is for
albuterol. We are moving forward in this direction
in light of the fact that there now exist two
alternative, non-CFC albuterol metered-dose
inhalers on the market in the U.S., that being
Proventil HFA and Ventolin HFA.
In addition, in 2003, the American Lung
Association submitted a citizen petition on behalf
of a group of organizations, collectively referred
to as the U.S. Stakeholders Group. That petition
requested that the agency move forward with this
rulemaking process in order to remove albuterol
from this list.
That citizen petition is included in your
background materials. Your background materials
also include other communications we received from
the Stakeholder's Group as well as the submissions
to the public docket that were submitted by various
interested parties and organizations in response of
the citizen petition.
So what are the currently marketed
albuterol metered-dose inhalers? Obviously, they
can be divided into those that contain CFCs, which
are ozone-depleting substances, and those
don't contain CFCs. In terms of the CFC MDIs,
there are several. First of all, there is the
branded product, Proventil, marketed by
Schering-Plough. This was approved in 1981. In
addition, there is a product marketed under a
Warrick label which is marketed under the same NDA.
Then there are several generic versions.
Actually, four have been approved. The first of
these was approved in 1995. Currently, three of
these are being marketed. As you may know, in
1981, there were actually two branded albuterol CFC
MDIs that were approved, the other one being
Ventolin. That is not listed here because it is no
longer marketed within the U.S.
Now moving to the non-CFC MDIs or, and I
will use the shorthand, as alternatives, these
don't use CFCs. Rather they use HFA 134A which is
a substance that does not affect the ozone layer.
There are two of these HFA products; Proventil HFA,
which was approved and initially marketed in 1996
and, more recently, Ventolin HFA, which was
approved in 2001 and was marketed in
So this is the regulation, obviously, that
is at the heart of today's discussion, 2.125,
called the Use of Ozone Depleting Substances in
Food, Drugs, Devices or Cosmetics. Among a number
of thing, one of the things that it does is it
lists specific drug moieties for which the use of
CFCs is considered essential.
In addition, as Dr. Meyer mentioned, it
sets forth criteria. There are four such criteria
that must be met in order to remove a drug moiety
from the list of essential uses.
I will run through these again. Dr. Meyer
has been through them. I will run through again,
though, because I think they are the heart of
today's discussion. First of all, and here I am
referring to active moieties represented by two or
more NDAs which is the case, as I mentioned, with
The first criterion for removing a drug
from the list of essential uses would be that at
least two non-ozone-depleting-substance products
that contain the same active moiety are
marketed with the same route of delivery for the
same indication with approximately the same level
of convenience as the ozone-depleting product.
The second criterion is that supplies and
production capacity for the alterative must exist
or be expected to exist at levels that would be
sufficient to meet patient need.
The third criterion is that adequate
postmarketing-use data should be available for the
non-ozone-depleting products. Again, as Dr. Meyer
mentioned, that is to provide some reasonable
assurance that no unanticipated limitation of the
alternative product emerges during the
postmarketing, so real-world experience that was
not detected prior to approval.
Then, finally, the fourth criterion is
that patients who medically require the product
would be adequately served by non-ozone-depleting
products containing the same active moiety and
other available products.
So now I am going to walk through each of
these criteria and look at how they apply
albuterol. The first criterion; again, at least
two products containing the same active moiety, the
same route of delivery, the same indication and
approximately the same convenience of use. So,
clearly, the alternatives that we are discussing,
Ventolin HFA and Proventil HFA, both have the same
active moiety, albuterol. Both are delivered by
the same route of delivery, oral inhalation, and
carry the same indication, prevention and relief of
bronchospasm and patients with reversible
obstructive airway disease and prevention of
I should point out the initial NDA,
Proventil, was approved down to the age of 12 and
Ventolin was approved down to the age of four.
Both of the alternative products are approved down
to the age of four.
Finishing up with the first criterion, the
final bit of it is the same level of convenience.
Now, when we looked at the same level of
convenience, we described, in the Preamble, various
aspects of what we might mean by
that. We looked
at things like portability, preparation before use
and the physical effort of manual dexterity that
might be needed to administer the drug.
The CFC and HFA MDIs are quite similar and
so have very similar portability and require
similar degrees of physical effort and dexterity to
use. I should mention, in regard to preparation
before use, that, in the early experience with the
first HFA that was approved, the Proventil HFA, we
became aware that there were occasional instances
of clogging of the actuator if they were not
Now, the CFC and the HFA inhalers have
actually very similar cleaning instructions. It is
just evident that patients using the HFA inhalers
need to pay more attention to the cleaning
instructions that are already in the label for both
The second criterion is a little bit more
difficult to definitively establish at this point.
This is the criterion that states that supplies and
production capacity for the alternatives
need to be
at levels that would be sufficient to meet patient
needs. At least in part, because of the price
differential between the generics and the currently
marketed FHA products, the market share for the HFA
products, at this point in time, is much smaller in
comparison than the market share of the CFC
So, if the CFC products were to become
unavailable suddenly today, the current supplies
and production capacity of the HFA alternatives are
not sufficient to meet patient need. That is
because, simply, that the manufacturers would need
time to ramp up production. However,
GlaxoSmithKline, in its statement in response to
the citizen petition submitted to the docket and
included in your background package has stated that
it is confident that additional internal and
external capacity can be installed to insure
adequate supplied and production capacity for
Ventolin HFA and that this could be accomplished
within twelve to eighteen months.
In addition to this statement
docket, GlaxoSmithKline and, also, Schering-Plough,
will be speaking today and I expect that at least a
portion of their comments may address specifically
The third criterion that we are applying
is that adequate U.S. postmarketing data be
available for the alternatives, again, looking for
unexpected real-world problems with the
alternatives. At this point in time, we have
Proventil HFA which has been marketed for seven
years and Ventolin HFA which has been marketed for
Apart from the early reports of actuator
clogging that I mentioned, the available
postmarketing use data does not suggest any
problems in terms of safety, efficacy, tolerability
or patient acceptance of these two alternatives.
Perhaps the most difficult of the criteria
to address is the fourth. This is the criterion
that states that patients who medically require the
ODS are adequately served by the alternative. This
term, "adequately served," is
fairly broad and it
encompasses a number of things.
Clearly, the most important is that the
available data on the alternatives must demonstrate
sufficient efficacy and safety and tolerability and
so forth such that the alternatives could be
considered reasonable replacements for the CFC
MDIs. This type of data was submitted with the NDA
and has accumulated in a postmarketing period and
seems to imply that the alternatives do meet these
But there is a further subtlety to the
adequately served phrase here and that is cost. As
Dr. Meyer mentioned, during the process of the ANPR
and the proposed rule, there were comments about
the effect of this rule on the price of
medications. In the Preamble, in the Federal
Register, the Preamble to the 2002 Amendment where
these criteria were established, the FDA clearly
stated that it will consider cost in determining
whether the alternatives meet patient needs.
So I am going to take a couple more slides
to just look at this cost issue a little
more depth. As with most drugs, branded CFC
products cost more than their generic counterparts.
As it turns out, in this very complicated
healthcare system that we have in the U.S. in which
the specific price of a medication varies according
to a number of factors including who is paying, it
is somewhat difficult to arrive at "the" price of a
Therefore, it is somewhat difficult to
arrive at a clear statement of the differential
between the cost of a branded product and a generic
product. Dr. Lutter will go into this in a little
bit more depth and talk about the various sources
of data that are available for the price of a
medication and how complicated that issue is.
I have provided on this slide some data
from an FDA website that highlights the cost
savings to a patient that can be achieved with
generic products. The web address is in your
handouts. On this site, data on the average
national retail price, which was data from IMS
Health, were used to generate this
that the retail cost per day for an asthmatic
patient who used Ventolin would be $1.44 whereas
the CFC generic would be 69 cents per day.
Of course, this is a comparison between a
CFC generic and a CFC branded, so it is important
to note the branded HFAs, in general, are priced
comparably to the branded CFC products although not
exactly the same price.
The other element to this is that there
are a number of existing patents and, due to these
patents, there are currently no generic HFA
products available. These patents are listed to
expire, the first one in 2010 and the final patent
in 2015. So, given the current realities, the
removal of the essential-use status of albuterol
would result in an increase in the price of
The public-health consequences of such an
increase in price are not known and are, in fact,
very difficult to predict. One possibility would
be that patients who are prescribed albuterol
metered-dose inhalers may be either
unwilling to pay for that and so may not purchase
the albuterol inhalers.
It is also possible that an increase in
the price of an albuterol MDI, which is an
acute-reliever drug from which patients, as you
know, perceive an immediate benefit, might result
in them forgoing filling prescriptions of other
medications such as asthma-controller drugs from
which they don't receive the same immediate
feedback. But, as you know, controller drugs are
quite important in the appropriate management of
So, as I mentioned, Dr. Lutter will
discuss in greater depth these economic aspects
including descriptions of the various sources of
price data that are available and means for
estimating how changes in the price of albuterol
MDI might affect the utilization.
As I mentioned, that is a difficult task
in and of itself, how will an increase in price of
an MDI translate into a change in utilization of
albuterol and, even if we were able to
that firmly, the next question that begs answering
would be how does the change in utilization
translate into important health outcomes. Of
course, that is an open question as well.
So, before I close, as I mentioned, I want
to bring up a couple of other issues that are not
directly responsive to the criteria in 2.125 but,
nonetheless, may be quite important in
considerations regarding a path forward on
albuterol. Both of these issues relate to the
future availability of chlorofluorocarbons.
The first issue has to do with production
facilities. Currently, the only source of
pharmaceutical-grade CFC 11 and 12 for use in the
U.S. is Honeywell's plant in the Netherlands. CFC
11 and 12 are the particular chlorofluorocarbons
that are contained in the albuterol CFC MDIs.
The Dutch Government has informed
Honeywell that CFC production at that factory will
no longer be permitted after 2005. So that might
jeopardize the supply of CFCs that are necessary
for the manufacture of albuterol MDIs but
of the other MDIs that use pharmaceutical-grade
CFCs. However, Honeywell has stated in its
submission to the docket in response to the citizen
petition that it will begin production of
pharmaceutical-grade CFC 11 and 12 at a U.S. plant
and will be able to supply CFCs beyond 2005.
Honeywell will also be speaking during the open
public hearing session today.
The second issue that touches on the
future availability of the CFCs refers to potential
actions that might be taken by the parties to the
Montreal Protocol. So, as Dr. Meyer mentioned,
each year the U.S. and other countries who request
to manufacture CFC MDIs, go through a nomination
process whereby specific quantities of CFCs are
requested of the parties.
Thus far, the parties have respected the
U.S. determination that albuterol is, in fact,
essential and have granted the volumes requested by
the U.S. However, more recently, the parties have
very pointed noted the availability of two non-CFC
alternatives within the U.S. and some
questioned the continued need for
chlorofluorocarbons for this purpose. It is not at
all clear how long the parties will continue to
grant CFC requests for use in albuterol MDIs.
So, with that, I will close. I have
listed on this slide the questions or topics for
discussion that have been provided to you in a
handout format. Essentially, the agency is asking
you to discuss the extent to which you believe the
criteria that are established in the 2.125 for
removal of a drug substance from the list of
essential uses of CFCs have been met in the case of
albuterol. Beyond that, we are open to hearing
from you any suggestions of additional data,
additional information or other issues you think
should be considered as we move forward in this
process of determining the essential-use status of
With that, I will close.
DR. CHINCHILLI: Thank you, Dr. Sullivan.
Again, we are ahead of schedule so we can take some
questions from committee members if there
questions. Yes, Dr. Atkinson?
DR. ATKINSON: Can you comment on whether
the existence of the patents on the new HFA devices
are going to preclude the development of any
generics until that time period? Are there any
pending applications for generic devices?
DR. SULLIVAN: Of course, we can't comment
on any pending applications. The analysis of
patents is a complex issue that the FDA doesn't
really directly do. Companies claim they have
patents which protect them. If a generic firm
wants to challenge that patent, they can. I think,
beyond that, perhaps I will invite Wayne Mitchell
to comment more specifically, if he can.
MR. MITCHELL: I really can't say much
more. We don't have any institutional expertise on
patent law. Patents are listed in our Orange Book.
The patents are listed through 2015. That is about
all we really can say.
DR. CHINCHILLI: Any other questions? Dr.
Sullivan, I have a question. In one of your
slides, when you talked about Proventil
said that early reports of actuator clogging were
available. Does that imply that there are no
longer reports of this problem? Were there
modifications to the device? I just was confused
by the word "early" reports of actuator clogging.
DR. SULLIVAN: That refers to the fact
that when the product first went on the market--and
it is not unusual to get more reports on a
particular drug when it first hits the market, but
the agency became aware that patients were having
problems with the clogging of the actuator and an
effort was made to better publicize the necessity
of cleaning these products because, although the
cleaning instructions were included in the CFC
versions, they may not have been followed by
It was determined that if the instructions
are actually followed, there are fewer reports. I
believe that the number of such reports has
declined. That was sort of an early phenomenon.
DR. CHINCHILLI: Thank you. Any other
questions? Okay; if not, then we will move on to
DR. LUTTER: My name is Randy Lutter. I
manage a small economics group within the Office of
Policy and Planning, Office of the Commissioner at
FDA. It is my pleasure to be here.
I would like to talk to you today about
the question of whether or not delisting albuterol
will have effects on--whether the patients will be
adequately served by delisting albuterol.
Let me begin by giving you an overview.
The key conclusion is that delisting albuterol CFCs
will deter the use of a number of prescribed MDIs
that is large in absolute terms but small relative
to the market. Our analysis is ignoring an
announced giveaway by GlaxoSmithKline of 2 million
MDIs per year because we lack a basis to evaluate
that quantitatively. We also find that the effects
on public health are too uncertain to quantify.
Let me give you some brief institutional
background of how an economist ends up in the
position of speaking before a group of
pulmonary and allergy advisors to FDA. There is an
executive order, 12866, signed by President Clinton
in '93 and it actually follows one signed by
President Reagan in '81. It directs the agencies
to assess the costs and benefits of all regulatory
actions developed through the notice and comment
rulemaking that Dr. Meyer described earlier.
The office that I had at FDA develops the
economic analyses required by that executive order.
The method of economic analysis that we developed
follows the constraints of OMB Circular A-IV which
is the latest in a series of circulars developed by
the Federal Office of Management and Budget
directing agencies on how to conduct economic
The executive order directs agencies to
assess the cost and the benefits and to take
regulatory actions which are cost-effective but
economics also is reflected in the decisions of the
Montreal Protocol. Drs. Meyer and Sullivan have
mentioned the term "essential," and "essential
use," turns on whether there are
technically and economically feasible alternatives
or substitutes that are acceptable from the
standpoint of environment and health and that is in
Decision IV-25. Section 2.125 uses the phrase
"adequately served." As described by Dr. Meyer,
that has economic content.
So there are actually three institutional
reasons why economics matters for the current
A brief discussion of economic
fundamentals. The issue here is that delisting
would remove albuterol MDIs with CFCs. Those are
currently the only generic albuterol MDIs on the
market. Therefore, one would anticipate on that
basis an increase in the price. So the broad
question is whether or not that increase in price
has effects on whether or not patients are
To comply with the executive order, we
need to assess the benefits of delisting and, in
particularly, a relatively earlier delisting as
opposed to a later one, and also the
The benefits come in four separable
categories. The first is a controlled transition.
You have already heard presentations about the
nature of the international cooperation and the way
that that might affect the availability of CFCs by
offering a relatively--by proceeding with this
rulemaking, FDA hopes to establish an opportunity
for a controlled transition to CFC-free MDIs.
The second category of benefits is clearly
the environmental ones that Dr. Meyer has
described. Reduced emissions would lead to
reductions in skin cancers, cataracts and
UVB-related ecological benefits. For this, our
proposal, FDA has not been able to quantify the
benefits in terms of skin cancers, cataracts or
UVB-related ecological benefits.
Some analysis in quantitative terms has
been conducted previously by other federal agencies
including the EPA. The difficulty that we face is
in translating their estimates of aggregate
benefits to the benefits from the much
reductions of CFC emissions that might be achieved
from this rulemaking, and we haven't been able to
do that for this proposal.
A fourth category of benefits pertains to
international cooperation. Dr. Meyer did not
understate in any way the importance of the
Montreal Protocol. It is a flagship treaty for
successful international environmental protection
and it enjoys wide respect and esteem for that
A final category of benefits is that this
rulemaking may encourage innovation in
environmental safe technologies.
In terms of the costs, I would like not to
focus on the increased spending associated with a
higher price of MDIs but, instead, focus on a
related question of whether or not the increased
prices may deter appropriate usage. I think that
is the appropriate issue for this panel and that is
the one that I am going to devote the rest of my
Also, by way of background in
key notion is what are we comparing the world to
when we do our analysis. We need to describe what
is the baseline relative to which we are assessing
the effects of delisting. The baseline in this
instance is the continued availability of generic
CFC albuterol. So the analysis that we are
conducting is relative to a world in which the CFC
albuterols continue to be available and, therefore,
the generic CFCs also continue to be available.
What I am going to focus on is a
relatively standard and conventional economist
approach to estimating the response to higher
prices. It really focuses, in particular, on the
estimated quantity of metered-dose inhalers that
may not be consumed as a result of the increased
price. It interprets this as the
product, really, of three things. One is the price
increase in percentage terms. The other one is a
measure of the consumer sensitivity to the price
increase, a measure the economists typically
describe using the word "elasticity," and, lastly,
the MDIs sold in the baseline to
consumers. So these are three parameters that I
will draw your attention to.
With respect to the price increase, the
prices are, of course, variable in a particular
way. The vary with market conditions and they vary
also in response to the marketing decisions made by
the different companies marketing the products. As
a result, the assessments of the price are
difficult not only because of the data deficiencies
but also because, ideally, we need to be looking
forward to what the price difference might be
between a world where the albuterol CFCs are
delisting and a world where they would continue to
That forward-looking approach requires and
association of these prices that takes the
variability into account. For the purposes of our
analysis, that is too complicated and we are,
instead, going to take the current price
differences as a measure of the price increases
from the delisting. The merits of this approach
are simplicity, transparency and also
with an announced policy of GSK that it would
freeze wholesale prices through December, 2007.
Where does one go for information on
prices? In the modern day, Google comes to mind as
a source of all information. If you go to Google
and look for prices, you come to drugstore.com. It
listed generic MDIs with albuterol on the 24th of
March for $14. HFA at drugstore.com sold a
Proventil. The Proventil HFA was sold at $39.61
and Ventolin HFA sold at $38.99. Those prices I
have checked twice and they were relatively
unchanged in the recent period.
That gives an increase of about 180
percent just comparing the generics to the HFA.
But these web-based prices are really
unrepresentative. They neglect the
brick-and-mortar outlets. They neglect shipping
costs. Ideally, what one would want are average
retail market prices for the cash-paying customers
who would be sensitive to price increases.
We have not acquired these idea data for
the analysis that we have conducted for
proposal. So, instead, I am going to talk to you
about data we have acquired which are the best
available proxies at this moment.
The Medical Expenditure Panel Survey of
the Agency for Healthcare Research and Quality
provides some information on prices. This survey
assesses expenditures by the noninstitutionalized
people age less than 65 in the non-Medicare
population. It provides information on the average
retail prices among all payer types, the insured
and the uninsured alike, for CFC albuterol inhaler
prescriptions 2000 to 2001.
The information is that the generics are a
little bit less than $25. I also report here the
standard error. The brand is $39. You have heard
Professor Sullivan mention that the branded price
of the CFC tends to be close to the branded price
of the HFA. In this instance, the data on the HFA
prices are too rare to report.
We also looked using the MEPS survey at a
sensitive population that lacks insurance or has
only private non-group insurance which,
judgment of experts at ARC would typically exclude
coverage for drugs. We looked among this group at
people with incomes less than 400 percent of the
federal poverty level. This was a convenient
cutoff, given the data constraints of MEPS.
Within this group, the estimated average
retail prices were $22 for the generic inhalers
and, again, in this instance, the data on the
branded inhaler prices were too rare to be
reportable. This group had about 2.8 million
albuterol prescriptions annually.
A second source of data on prices that we
consulted is proprietary information from IMS
Health, their national prescription audit for the
first quarter of 2004. Note the distinction in
dates. The MEPS is 2000-2001 and this is 2004.
There is no more recent information on MEPS. For
the IMS price information, we have prices measured
using the average pharmacy's revenues from
uninsured customers, insured customer and Medicaid
beneficiaries alike. So this is basically across
all payer types.
This includes chain, independent,
food-store pharmacies. It excludes the Internet.
It excludes mail-order and long-term-care
Information on prices from IMS suggests
that the median price for the generic albuterol
MDIs is $19.70 and for the albuterol HFA MDIs, the
price is $43.00, the price difference of about
$23.00. This suggests an increase of about 120
It is important to view these data as
approximate for a variety of reasons. I have
acknowledged the proxies for the conceptually
correct measure. In addition, the HFA prices have
been changing. The MDI data suggests that there
has been an increase of about 18 percent over the
twelve months preceding the sample of the first
quarter in 2004. Again, these prices reflect the
full price for the insured and the uninsured alike.
The next part of the puzzle is to assess
the response to the increase in price that one
might expect among consumers. In general, there is
an extensive economics literature that reports
small effects of price increases on consumption.
It rarely distinguishes, however, among drugs.
There is a very recent article by Dana Goldman of
Rand in JAMA that surveys more than a half million
people in 52 health plans over four years.
interestingly, it reports responses to
increases in co-pay among different categories of
medicines. With respect to anti-asthmatics, as the
average co-pay for anti-asthmatics doubles, the
average number of days of treatment supplied fell
by more than 30 percent. The authors report that
albuterol was the most common anti-asthmatic
including albuterol sulfate.
They also assess the effects on public
health. Let me back up a moment. They also assess
for drugs with no OTC substitutes, the set that
presumably includes albuterol MDIs. The response
in utilization described as I just did in the
average number of days of treatment supplied is
0.15. So there is substantial uncertainty about
what would be the relevant number.
With respect to average co-pay for
anti-asthmatics as a group, the response is 0.3.
But, if one then looks at drugs with no OTC
substitutes which would also include albuterol, the
effect is 0.15.
The authors go on to talk about the effect
of these increases in co-pay on ER visits and on
hospital days for the class of drugs diabetes,
asthma and gastric-acid disorder together, ER
visits grew by 17 percent and hospital days by 10
percent when co-pays doubled. The authors
acknowledge that these results are "not definitive"
for reasons of data limitations.
As a result, we are unable to quantify any
effects on public health because of the nature of
the limitations to the data.
Let me offer a summary of what we know
about the response to a price increase. I have
mentioned that an analysis would have, really,
three parts. With respect to the MDIs sold to a
price-sensitive population, MEPS suggests that
there are 2.8 million MDI albuterol
going to the uninsured patients with incomes of
less than 400 percent of the poverty line who are
not Medicare eligible and under age 65.
If one takes, instead, data from the
National Health Interview survey and combines that
with data on the distribution of MDIs as described
in the proposal, one ends up with a larger number
of MDIs that would be used by the price-sensitive
With respect to the price increase, we
really have two estimates. One is 120 percent
increase. That is from the IMS National
Prescription Audit reflecting average prices for
all payer types including those that are insured.
We also have the 180 percent which reflects the
A key question pertaining to the analysis
is the estimated elasticity, or the nature of the
consumer response. JAMA, as I mentioned, reports
two numbers that may be plausible. I think the
0.15 is one that we focus on. That reflects their
estimate of the response to increases in
drugs with no OTC substitutes. I think that is
also consistent with other economics literature.
The next question pertains to the
interpretation of these. The JAMA paper really
focuses on consumer response for insured patients
to higher co-pays. They report an average co-pay
of a little bit more than $12. So that co-pay and
the increase are roughly the same order of
magnitude as the price and the price increase that
one would anticipate for uninsured patients.
So, if one applies that increase in price
implicit in both the IMS data and in the Internet
data and the consumer response implicit in the JAMA
paper to the MDIs sold in the price-sensitive
population, then it is reasonable to infer a
quantity response among the uninsured population in
the high hundreds of thousands. It is very
difficult to be more precise. This is a daunting
exercise with data that are imperfect, as we have
acknowledged. But the numbers that we have
presented in particular are 0.4 million to 1
These are clearly approximate.
Let me offer some empirical caveats. I
have neglected the response of insured patients to
any increases in co-pays. The JAMA paper measured
these and we know that the co-pays for branded
products are much higher than co-pays for generics.
But this delisting of albuterols would have no
direct effect on the co-pays. The co-pays may
change only in response to the changes of the
insurance companies. We, therefore, believe these
are too uncertain for us to quantify at this time.
Let me reiterate that the estimates of the
price-sensitive population of the price increase
and the consumer response, or the elasticity, are
all relatively uncertain.
There is another caveat with respect to
the interpretation of these estimates.
GlaxoSmithKline wrote to FDA on May 3 of 2004
stating that 2 million complementary samples of
Ventolin would be made available each year to
physicians who may choose to reserve these inhalers
for their lower-income patients.
We are unable to assess
what this might do for any reductions in
utilization because of the uncertainty associated
with how they might actually be distributed in
physicians' offices. The GSK letter also said that
it would freeze wholesale acquisition costs or
prices thereby suggesting that the eventual HFA
prices at the retail level would also be relatively
constant. As I have mentioned, that is an
assumption that we maintain.
The giveaway, in general, may
significantly offset the loss of canisters provided
it is well targeted to the most price-sensitive
Thank you for the opportunity to talk. I
would be happy to take questions.
DR. CHINCHILLI: Thank you, Dr. Lutter.
Are there any questions from the committee? Dr.
Questions from the Committee to the Speakers
DR. SCHATZ: My question is the
relationship between elasticity and
over-the-counter substitutes. I gather that, with
more over-the-counter substitutes, then elasticity
is theoretically increased?
DR. LUTTER: Yes.
DR. SCHATZ: Then I would submit that
there may be an over-the-counter substitute which
is Primotine so that I think that, in
consideration, one might have the higher elasticity
and that patients doing that might be not as well
DR. LUTTER: Lacking your medical
expertise, I will leave the judgment and the
discussion about the substitutability of the OTC to
you. Let me simply say that the availability of
OTC substitutes would affect the response in that
DR. SCHATZ: And it could make the higher
value that they found more relevant than the lower
DR. LUTTER: Yes.
DR. CHINCHILLI: Dr. Martinez?
DR. MARTINEZ: Certainly with the caveat
which we may discuss later, but Primotine
albuterol and, thus, a potential consequence that
has not been thought of is that individuals who
cannot afford albuterol anymore will start using
over-the-counter Primotine which is associated with
a completely different set of side effects which
need to be seriously considered.
DR. CHINCHILLI: Ms. Schell, you had a
MS. SCHELL: Yes, thank you. I just have
a question about the shift of production of the CFC
to the United States from the Netherlands in 2005.
Do you project an increase in the CFC MDIs' cost
with that shift of production coming to the U.S.?
DR. LUTTER: That is not something we have
taken into account in the analysis. We have no
information on which to assess that question.
MS. SCHELL: Thank you.
DR. CHINCHILLI: Do any of the FDA
representatives want to respond to that or the
DR. MEYER: I think, as far as that
question--I don't think we have data that
one way or the other. Not the least of the
considerations there is how much in the price does
the actual cost of CFCs play, and I don't think we
As far as the earlier question and point,
I think it is something we can certainly consider
as we consider all the input from today.
DR. CHINCHILLI: Dr. Swenson, you had a
DR. SWENSON: Yes. Regarding that JAMA
article, did you pursue at all the cost
implications of this greater ER and hospitalization
rate that might arise from some of these shifts
that you have postulated?
DR. LUTTER: No, largely because of the
uncertainty in quantifying those increases. As I
mentioned, there were three categories of
therapeutic classes that they grouped together only
one of which was asthma. Albuterol is only one
treatment for asthma and, therefore, we thought
that inferring--that the judgment of the
applicability of those estimates to this
appeared to--is that we have no basis to accept
those estimates to predict quantitative reductions,
quantifiable reductions, in the ER visits or days
in the hospital. So, therefore, we don't really
want to estimate either the cost of reductions or
increases associated with those either.
DR. CHINCHILLI: Dr. Moss?
DR. MOSS: I work at Grady Memorial
Hospital which serves an indigent-care patient
population. About 40 percent of the patients there
are self-pay which means they don't have insurance.
It is nice way of saying that. One of the big
problems in the hospital is the in-hospital
pharmacy costs. Do you have any information or is
there a way to figure out how the changing cost of
inhalers would affect operating at a hospital that
serves indigent-care patients or is there a way to
figure that out?
DR. LUTTER: There probably is a way to
figure it out. It is not something we have done.
DR. CHINCHILLI: Dr. Kercsmar?
DR. KERCSMAR: The transition to HFA
inhalers has been made in a number of other
developed and industrialized countries. Are there
any data that are comparable to that that has been
published in the JAMA article? You referenced that
might give other insight into the elasticity
problem, changes in morbidity, lack of prescription
refills or, because of the difference in economic
structure and drug reimbursement in these
countries, are there no data available? Are there
lessons to be learned from countries that have
already made the transition?
DR. LUTTER: It is a good question. We
thought of that. Other countries lack the
uninsured population that exists in the United
States and generally control prices. In
particular, the price discrepancy that I have
described here is unusual if not unique.
DR. CHINCHILLI: Any other questions by
the committee members for Dr. Lutter?
MR. MITCHELL: Just before the break there
is something I would like to say.
DR. CHINCHILLI: Yes; please go ahead.
MR. MITCHELL: This is addressed to the
people who are watching this procedure through the
webcast. The proposed rule that we have been
discussing is available on FDA's website if you go
to www.fda.gov. In the middle column, you should
see FDA advanced display. If you click on that,
you should be able to see another link which goes
to advanced publication display. Click on that and
you should see something about a special filing,
publishing, on June 16, 2004. That should get you
to the Notice of Proposed Rulemaking.
Thank you, Mr. Chairman.
DR. CHINCHILLI: Thank you, Dr. Mitchell.
Yes; Ms. Schell?
MS. SCHELL: I am not sure who to direct
this question to, but I have a question. Several
of you talked about what the ozone depletion does
in cataracts, skin cancer and that, but no one has
mentioned how it affects asthmatics of COPD
patients, the depletion of the ozone layer and how
that would increase, if we didn't do something now,
how the ozone depletion would affect
the future. Would we be causing more asthmatics to
have problems with their breathing?
DR. MEYER: I will try to answer that. I
think it is unclear to us that asthma or COPD
patients would be differentially affected in terms
of the environmental consequences of ozone
depletion. You were not asking this, but, for the
public, I think it is hard for them to understand
that ozone in the lower regions of the atmosphere
is bad for asthmatics, particularly, and probably
for COPD as well. But ozone in the stratosphere
probably has no bearing on the development of
asthma and COPD that we know of.
So we would assume that the consequences
to the asthmatic and COPD population would be the
same as to consequences to other populations. One
could perhaps try to parse that out more closely in
that it is potential that inhaled corticosteroids,
for instance, may somewhat increase the
predisposition to cataracts. Whether that would be
even more the case in the circumstances
thinned ozone layer, who knows. But, again, we
have no basis at this point to believe that there
would be a differential effect on those patients.
DR. CHINCHILLI: Any other questions from
committee members for our FDA representatives?
DR. MEYER: I just wanted to make the
point--I realize that the people sitting around
this table probably are fairly well versed in this
but, for the purposes of the public, I realize that
we didn't really sort of step back and make this
point. But albuterol has really become a prime
drug for both the treatment of asthma, in
particular, but also for COPD in a way that, even
when we began the advanced notice of proposed
making in '96, I don't think we have fully
It is now clear that approximately 50
million or more canisters of albuterol are
necessary to treat patients with asthma and COPD in
the United States. It is, again, by far and away
the bronchodilator or short-acting
choice in patients with asthma and COPD.
Again, I think the people around the table
know this but, for the matter of the public record,
I just wanted to get on the table the kind of
numbers we are talking about. This is a very
important drug that is sold widely and is really
critical in the asthma armamentarium and very
important in the COPD armamentarium as well.
DR. CHINCHILLI: Thank you, Dr. Meyer.
DR. MARTINEZ: I have one question
regarding worldwide distribution of sales. What is
the situation in the underdeveloped world? Which
are the products that are sold there and what are
the projected consequences of this regulation in
that particular market?
DR. MEYER: From the FDA perspective, I
don't think we have a lot of information on that.
I also am involved in the Montreal Protocol on a
working group on aerosols, medical aerosols. I can
say that the United States actually exports
relatively few of its MDIs as opposed to
where much of their production is exported.
So most of what we are talking about here
is for domestic consumption and will not really
have much bearing on the rest of the world. I
would parenthetically note that there is a lot of
attention paid in the Montreal Protocol about how
this phase-out in the developed world will affect
that in the developing world because it is a very
Unfortunately, in much of the developing
world, the use of MDIs is not very common because
they are--although they are cheap per dose, to
actually buy one requires you to buy a certain
number of doses as opposed to oral medications
which may be more expensive per dose but cheaper
where you can just buy a few.
So there is probably undertreatment in the
developing world in general and specifically there
is not a lot of use of MDIs relative to the
DR. CHINCHILLI: Before we proceed with
other questions, I would like to welcome
to the committee. Would you turn on your
microphone and introduce yourself to everyone?
DR. REISS: Sure. I apologize for being
late this morning. I am Ted Reiss from Merck
Research Labs. I am the industry non-voting
representative on the committee.
DR. CHINCHILLI: Thank you. Any other
questions? Yes; Dr. Swenson?
DR. SWENSON: Dr. Meyer, a couple
questions. I didn't see anywhere in the data,
either in the background information, if you could
go back to the initial signing of the protocol. At
that point, how much CFC was being produced and
now, of that amount, what does the present use of
CFC in albuterol represent in a percentage term or
DR. MEYER: I am sorry that I don't
actually have those particular figures available.
I can say that the use of CFCs for MDIs when the
protocol was signed was a relatively small
proportion of the CFC use because CFCs were then
used in refrigerators, auto air
air conditioners, foams and so on.
Now that the provisions of the Copenhagen
Amendments went into place, the use of CFCs for
MDIs in the developed world is the large majority
of these CFCs but it is still a small fraction
compared to what was the total in 1987.
Albuterol in both the United States and in
the rest of the world has been a prominent use of
CFCs. As I mentioned, for the United States, it
amounted to about half, or does amount to about
half, of our essential-use denomination. So I am
not giving you specific numbers, but I hope I am
sort of giving you a qualitative feel.
DR. SWENSON: Okay. The next question I
have then is, on Slide 24 or one of the similar
slides that you had in your talk, was the projected
return, or this idea of a projected return, of
normal stratospheric ozone levels by mid-century
based on the present use right now which includes
our use of CFCs or was that based on complete
elimination of CFCs?
DR. MEYER: Those projections, and just to
be clear, they are actually projecting the recovery
to early 1980s levels which was still not normal
but a recovery nonetheless, are based on the
successful conduct of the Montreal Protocol. So it
is based on the Montreal Protocol as currently
amended being successfully carried out into the
DR. CHINCHILLI: Ms. Schell?
MS. SCHELL: I am sorry. I would like one
more question on the 50 million uses of Ventolin or
albuterol. Have you looked at the overuse of
albuterol and the underuse of the
anti-inflammatory? Is there any look at overuse?
As we know, asthmatics, a lot of the time, don't
have the proper education in the use of the
anti-inflammatory so they overuse their albuterol.
Are there any numbers reflecting that?
DR. MEYER: We do not have such numbers.
It is certainly something that we considered. As
Dr. Lutter said, there are a lot of things we would
wish to consider in an ideal
analysis. One of the
complications of projecting a public-health
consequence of some drop in the number of albuterol
MDIs distributed or used relates to these
questions, relates to the possibility that when
beta-adrenergic bronchodilators are overused that
that might, itself, have detrimental effects.
But these things, although clearly we
think about them, are not something we can
reasonably quantitate. So we have not.
DR. CHINCHILLI: Any other questions from
the committee? If not, I want to thank the FDA for
enlightening us on these issues. We are scheduled
for a break at 10:00. We are about eight minutes
before that, so we will take the break early. But
I would like to reconvene at 10:10.
DR. CHINCHILLI: I do have one
announcement and that is if you have a cell phone
and it must be on, it would be preferable if you
put it on vibrating mode and then, if it does go
off, that you take your call outside the
Before we go on to the open public
hearing, the first session that we will have this
morning, I just want to make sure that the
committee members don't have any other questions
for the FDA representatives. Are there any other
questions from the committee? Any final comments
from the FDA?
If not, then we are going to move into the
open public hearing.
Open Public Hearing (Session 1)
DR. CHINCHILLI: One other announcement I
am supposed to make. Both the Food and Drug
Administration and the public believe in a
transparent process for information gathering and
decision making. To ensure such transparency at
the open public hearing session of the advisory
committee meeting, the FDA believes that it is
important to understand the context of an
For this reason, the FDA encourages you,
the open public hearing speaker, at the
of your written or oral statement, to advise the
committee of any financial relationship that you
may have with any company or any group that is
likely to be impacted by the topic of this meeting.
For example, the financial information may
include a company's or a group's payment of your
travel, lodging or other expenses in connection
with your attendance at the meeting. Likewise, the
FDA encourages you, at the beginning of your
statement, to advise the committee if you do not
have any such financial relationships.
If you choose not to address this issue of
financial relationships at the beginning of your
statement, it will not preclude you from speaking.
So that is important for our open public
hearing speakers to recognize that and to make
acknowledgments. I probably will repeat this
statement when we start the afternoon session as
We are ready for our first speaker during
the open public hearing. Please be sure to
introduce yourself and pay attention to
statement I just made.
MS. WEXLER: Good morning. I am Pamela
Wexler. Since 1997, I have served as attorney and
advisor to the U.S. Stakeholders Group on MDI
transition. I have no financial interest in any of
the companies or participants today.
I would like to start by telling you a
little bit about the U.S. Stakeholders Group. It
is a consortium of nine leading patient and medical
professional organizations. Members of the
organizations include patients with asthma, chronic
obstructive pulmonary disease and other respiratory
diseases. Collectively, the member organizations
represent and reach 25 million Americans who suffer
from asthma and other respiratory diseases and they
include organizations that educate and advocate for
individual patients and their families through
Members of the Stakeholders Group also
include physicians, respiratory therapists and
other healthcare professionals who specialize in
respiratory care and they are recognized
among the healthcare community. The stakeholders,
as a group, and its member organizations
individually collaborate with various other
interested organizations in the U.S. and around the
In the eight years since the Stakeholders
Group has acted formally, neither its membership
nor its procedures have changed. The American Lung
Association convenes the U.S. Stakeholders Group.
The member organizations elect representatives to
the stakeholders process and these individuals
meet, in person, once or twice a year and
Oftentimes, the leadership of these
organizations attends stakeholder meetings and
participates in the deliberations. Other times,
the government and the private sector are invited
to attend as well and make presentations. Any
action taken under the name of the stakeholders is
approved by each member organization.
Now, I would like to turn to our petition.
Eighteen months ago, we petitioned FDA to
albuterol essentiality. The petition was not
precipitous. It, in fact, was requesting the
agency merely consider essentiality. It was FDA,
itself, in a rulemaking process that started in
1997 and lasted five years that set up these
essentiality criteria, the conditions under which
any drug substance would be delisted and no further
CFCs would be available.
The stakeholders petition asserted that
the criteria had been met or, with the case of
manufacturing capacity, that the criteria could be
met or that information could be ascertained and,
hence, it was time for FDA to consider removing the
Now, there are a number of reasons why the
stakeholders petitioned FDA. I will just take a
moment to touch on them. First and foremost is the
environmental imperative. I won't spend too much
time on this because I think that the importance of
repairing the ozone layer is well established, both
by the Montreal Protocol and the U.S. Clean Air Act
on which, by the way, the U.S. has been a
since the beginning on the international process.
FDA, in its July, 2002 Final Rule establishing the
essentiality criteria actually offered a very
concise and clear explanation of why every use of
CFCs must be eliminated, even seemingly small
amounts like those used in MDIs.
I won't spend too much time on the second
sub-bullet either because a physician from one of
our member organizations in the next session, later
this afternoon, will present more on the
opportunity to improve disease management. But let
me just say that, from its inception, the
stakeholders position on the potential of
transition has not changed and that is that we
understand the potential of a switch in medication
and we have worked, and we hope to continue to
work, to ensure that that experience provides an
opportunity to improve patient care.
On the third and the last, and probably
the most pressing, issue for patients and
physicians is the issue of CFC supply and how it
might affect the availability of
medications. As I
am sure you will hear more about today, the future
of CFCs to make MDIs is uncertain and fundamentally
the stakeholders want FDA to sufficiently plan for
that and for CFC-free medications to be available
and widely accepted before CFC supply can have any
impact on product availability or price.
Since the petition was filed, in the
eighteen months since the stakeholders filed the
petition to consider albuterol essentiality, a lot
has changed and we have learned a lot more. As to
supply, anyone who follows this knows that, in the
past three to five years, there has been a lot of
new and often conflicting information about where
PhRMA-grade CFCs were going to come from after
December 31, 2005.
Remember, that is an issue simply for the
U.S. market because, for the most part, developed
countries will not need these chemicals after that
date. They are on pace to phase out the use of
CFCs in MDIs.
The stakeholders have never had full
information on the future of CFC
supply. We heard
originally, maybe two years ago, there were going
to be two plans, one in Europe and one here. They
we heard that that wasn't going to happen. Then
the issue of certification was raised, that plants
had to be certified, the CFCs produced had to be
certified, and that the production that would
replace the production that is going to be lost in
Europe would be a different kind of production and
that different specifications would be required.
We heard, now, recently, despite a letter
from Honeywell indicating its stated intent to
supply CFCs at a plant in Baton Rouge, Louisiana,
that we still had questions about certification as
that was not mentioned in the letter and we have
never heard anything further about FDA on what,
exactly, that requires.
So the stakeholders, themselves, have
limited information on which they could base a
conclusion that the CFC supply would be without
problems. Recently, a non-governmental
organization, NRDC, wrote the EPA suggesting that
it would be illegal to produce CFCs in
So, again, we are faced with not a lot of clear
information on how we will go forward.
As to the second sub-bullet, even if the
Baton Rouge plant is not a problem, we certainly
see an increase in pressure on the part of the
international community to limit future supply of
CFCs especially where there are alternatives as in
the case of albuterol. We heard recently that the
U.S. request that was recently put into the parties
was approved but with the strong suggestion that
the U.S. come back to the parties after this
rulemaking was complete since it wasn't clear that
those quantities would be needed.
So it is obvious that the parties are
signalling the intent to stop authorizing new CFC
production for MDIs, again, in the case of a drug
like albuterol where there are safe alternatives.
Also, since the petition was filed, we
have, in the FDA docket, an independent analysis
conducted by National Economic Research Associates,
NERA, that provided us a much better picture of the
albuterol market. I expect that we will hear more
about the NERA analysis this afternoon, but it gave
us a very good picture of how the market is
supplied, how patients who rely on albuterol pay
for their drugs.
It estimates the price and what the market
might look like once HFA alternatives are
introduced. More importantly, NERA projects how
the increased costs might be distributed and
allocated among the different classes of patients,
managed care and other payers including Medicare
Now, you know, the stakeholders are
medical and patient advocates, medical
professionals and patient advocates. We are not
economists. So we aren't here to speak to the
specific numbers in the NEAR report but we do
believe that the general thrust of the report
comports with what we have always believed about
the albuterol market and our understanding of how
increases, not just in medications but in all sorts
of other medical procedures and services rise and
are absorbed in the healthcare system.
Now, there is no mistake about the need to
ensure patient access to medication. In our
petition to FDA, we were clear that FDA needed to
take into account price and how it would affect
patients and their ability to obtain medication and
comply with their treatment regimens. But we think
that, between the manufacturers, the stakeholders
and FDA, collective, we can adequately protect the
potentially at-risk subgroups and we can do it in a
variety of ways.
On the part of the manufacturers, we have
one submission already in the docket from an HFA
manufacturer outlining what it intends to do. We
would hope that we would see similar commitments
from other manufacturers as we move forward about
increasing the number of samples and enhancing
On the part of the stakeholders, our
member organizations are committed to working with
the agency and the manufacturers to develop an
educational strategy for communicating the
availability of free and discounted
can work with our member organizations and our
network to deploy these messages in advance of
transition to patients, to specialty, general
physicians and the rest of the healthcare
As for FDA, we think that there also might
be mechanisms that the agency can consider to
protect, again, these potentially at-risk
populations. One thing we have discussed within
stakeholder meetings is for FDA to monitor the
patient compliance or access to HFA albuterol and
reserve the right to allow a certain number of CFC
MDIs to be sold in the case of a real emergency so,
if you will, a phase-down process that allows the
potential--and that is the potential in both CFC
supply and manufacturing capacity to not be gone
before we are out of transition, so a phase-down
period that protects that at-risk population.
I think that if FDA acts in a relevant
timeframe, there would still be enough stockpile to
be able to incorporate such a mechanism.
Last, I would like to turn to
of transition. There has been a lot of talk about
when the right time is. Now, it is no secret that
the stakeholders have long supported December 31,
2005 as the effective date for removing CFC
albuterol from sale in the U.S. As early as 1996,
in fact, before we had ever heard the word "TEFA"
or "WEERT," we embraced the idea of a target date.
We embraced the eventuality that these
chemicals as slated for elimination. We understood
that it was useful to have a target date so that
manufacturing capacity could be put into place.
That idea of an aim, a target, a goal, has proven
successful as is evidenced by the fact that the
rest of the world or the rest of the developed
countries also adopted that date and or on pace to
We saw transition as an opportunity to
educate physicians and patients about the learning
that has been done, especially in the last decade,
regarding asthma treatment and management.
But, in 1996, we saw December 2005 as a
goal, not an imperative. Eight years later, we now
know that WEERT will close. We know there are
additional uncertainties regarding the Baton Rouge
facility. We know that there are two alternatives
ready to go and a third on the way. Given that,
December 31, 2005 makes a lot of sense.
Again, I just want to go back to
mechanisms for actually proceeding through
transition. Ending at December 31 is sensible and
it is achievable and, most importantly, it is
near-term enough that any problems with HFA
production, any problems with patient access, any
problems with affordability, compliance, any
unforeseen consequences, can be discovered and
addressed before CFCs are unavailable and before
the capacity to produce additional CFC products is
Thanks very much.
DR. CHINCHILLI: Thank you very much.
We will move on now to our second speaker.
DR. JONES: Good morning. My name is
Elaine Jones and I am Vice President of U.S.
Regulatory Affairs at
GlaxoSmithKline. On behalf
of GlaxoSmithKline, I would like to thank the
advisory committee and the agency for opportunity
to present our commitment to the transition from
albuterol CFC-free metered-dose inhalers, or MDIs,
which are ozone-depleting to albuterol HFA MDIs,
which are non-ozone-depleting.
Principally, during this presentation, I
will address the two questions that have been posed
to us by the agency that relate to the FDA's
criteria for transition.
The first question concerns our
manufacturing capacity for Ventolin HFA and the
second, what GSK programs are, or will be put in
place to help ensure that patients are adequately
served during the transition from albuterol CFC to
albuterol HFA and thereafter.
To set the stage for discussion of the two
principle questions, I would like to review the
timing of Ventolin HFA development in relation to
implementation of the Montreal Protocol.
Development of Ventolin HFA started before the
Montreal Protocol was ratified and
submission of a new drug application in 1998.
Filing of this NDA was the result of over ten years
of research and development including a technically
challenging reformulation effort under
comprehensive clinical program.
After gaining FDA approval, GSK launched
Ventolin HFA in 2002 and stopped the sale of
Ventolin CFC. Currently, GSK sells Ventolin HFA in
165 countries around the world which has resulted
in over 20 million patient years of experience.
Also, in 2002, FDA published its final rule
outlining the criteria for transition from CFC
MDIs, which was the culmination of a lengthy
process that took five years to complete.
Quoted on this slide is one of the
criteria for transition from the 2002 Final Rule.
FDA has asked us, as one of the manufacturers of
the replacement products for albuterol CFC MDIs to
address this criterion which relates to the issue
of adequate supply and production capacity.
Specifically, the question is, can GSK, in
conjunction with other manufacturers of
replacement albuterol product, manufacture
sufficient quantities to satisfy patient demand
after the CFC products are no longer available.
To help answer this question, here is a
graphical representation of GSK's manufacturing
capacity over time in relation to the overall
albuterol market. Other manufacturers can be
expected to contribute to the supply as well. At
present, patient need for albuterol MDIs is about
50 million per year, as shown by the yellow shading
in this graph. This demand has remained fairly
constant over the past five years and is expected
to remain constant into the future.
The blue shaded portions of the graph
represent two distinct components of GSK's ability
GSK's ability to contribute to meeting this demand
with CFC-free MDIs. The darker shaded blue area
reflects currently installed capacity and the
lighter shaded blue area reflects expansion
capacity. The sum total of both components is
about 30 million MDIs per year, or about 60 percent
of the expected market.
Now, I would like to discuss in detail our
current capacity. GSK manufacturers Ventolin HFA
at a facility in Zebulon, North Carolina, which has
a long history of manufacturing MDIs including the
now discontinued Ventolin CFC. At this facility,
we already have installed the capacity to
manufacture 15 million Ventolin HFA MDIs. At
present, since transition has yet to take place, we
are utilizing only 2 percent of our installed
Production of up to 5 million MDIs could
be achieved immediately and this could be
progressively increased to the full 15 million MDIs
within six to twelve months. To achieve this
capacity is a relatively straightforward process.
We would need to hire additional staff and
reconfigure existing space.
As illustrated on the graph I presented
earlier, GSK is prepared to increase production
capacity by an additional 15 to 18 million MDIs.
This would entail significant capital investigation
on the part of GSK, would take approximately
to eighteen months to complete and would require
the installation of additional manufacturing
equipment and securing of MDI components.
This could be undertaken simultaneously
with a previous increase in production. This
expansion, in addition to our current capacity,
would deliver a total of approximately 30 million
I would now like to address the second
question posed to us by the agency which concerns
another one of the criteria in the 2002 Final Rule
on Essential Use Determinations and is reflected on
this slide. The issue is whether a high-priced,
non-ODS, product is effectively unavailable to a
portion of the patient population because they
cannot afford to buy the product.
Payers, and the healthcare system overall,
may experience higher costs as the market
transitions to CFC-free albuterol. But the
relevant question under FDA's 2002 Final Rule is
how individual patients will be impacted by this
transition, specifically whether they
adequate access to CFC-free formulations of
The larger policy questions regarding a
balancing of societal cost against environmental
benefits have already been resolved by the Montreal
In order to assess the economic impacts of
an albuterol transition, GSK commissioned a study
by the National Economic Research Associates. The
analysis proceeded on the basis of data collected
from a variety of sources as shown on this slide.
Although the economic report examined impacts on
payers as well as patients, our focus today is on
the impact a transition will have on the access to
albuterol HFA MDIs for individual patients.
To understand the impact on patients, one
must appreciate that albuterol is dispensed to
patients in different settings including retail
pharmacies, hospital pharmacies, clinics and
federal healthcare facilities. As represented by
the large green slices of pie chart, 84 percent of
dispensing takes place at retail
remaining 16 percent takes place in other settings;
for example, a Veterans Administration Hospital
where financial impacts on patients, of changes in
drug prices, are likely to be quite limited.
The pie chart on the right reflects a
further breakdown of the retail-pharmacy segment.
Within the retail portion, 72 percent of MDIs are
covered by private drug insurance and 15 percent
are covered by Medicaid. About 13 percent of
albuterol MDIs dispensed by retail pharmacies go to
patients who pay cash. GSK recognizes that it is
within this group of patients that the greatest
concern exists regarding access to albuterol MDIs
after a transition.
As we consider the patients who pay cash
for their prescriptions, it is important for us to
emphasize our long-standing dedication to helping
those in need obtain access to our medicines. For
over two decades, GSK and its Heritage Companies
have been committed to helping patients without
public or private drug insurance to get the
medicines that they need. To this end, we have had
in place various patient assistant programs.
I will now describe Bridges to Access, the
GSK program which is directed at patients of all
ages who require financial assistance. For those
who qualify, GSK offers its medicines, including
Ventolin HFA, at no cost or at a minimal
retail-pharmacy dispensing fee.
Individuals with annual incomes up to
$25,000 or families at or below 250 percent of the
federal poverty level are eligible for Bridges to
Access. Patients who enroll can receive their
medication the same day that it is prescribed.
This program also includes a spend-down option that
allows patients to deduct medical bills from their
income for purposes of determining eligibility
Patients are not required to be U.S.
citizens to qualify for Bridges to Access.
Patients who apply also receive assistance in
finding additional healthcare programs for which
they qualify such as Medicaid, AIDS drug-assistance
programs, state children's health
state elderly drug-assistance programs.
In this visual illustration, we use the
federal poverty level as a baseline to compare the
income eligibility levels for Medicaid and Bridges
to Access. The yellow line represents the federal
poverty level income for households of different
sizes ranging from one to four members. The blue
lines represent the average income eligibility
ceiling for Medicaid which is 135 percent of the
federal poverty level.
Each orange bar represents the maximum
qualifying income under Bridges to Access for a
household of that size. This maximum qualifying
income level is $25,000 for households with one
individual or 250 percent of the federal poverty
level for households with more than one individual.
I might add that certain patients who do
not meet Medicaid's eligibility requirements
despite meeting the income requirements could
potentially qualify for Bridges to Access. For
lower-income patients who do not have public or
private drug insurance, for whatever
Bridges to Access is, thus, a valuable resource.
GSK's experience with Bridges to Access
for Ventolin HFA from June 2003 to May 2004
illustrates the program benefits for patients. We
have distributed nearly $3 million worth of product
representing approximately 100,000 inhalers to
nearly 14,000 patients. During this period of
time, the total amount of Ventolin HFA distributed
was approximately 400,000 MDIs which means that one
out of four Ventolin HFA MDIs went to a Bridges to
GSK has generated awareness of this
program through various avenues including half a
million letters sent to advocates at the launch of
the program, training for healthcare providers and
partnerships with public agencies and professional
associations. In addition, we maintain a public
website with extensive information about our
program including application forms.
These activities represent some of the
significant efforts GSK has made to raise awareness
of the program and we look forward to
our outreach efforts. We are committed to provide
Ventolin HFA to all eligible patients in the event
of an increased need at the time of transition. In
order to show more clearly the estimated financial
impact of a transition to CFC-free albuterol on
individuals, I would like to now illustrate how a
lower-income patient might fare in a transition
both with and without the benefit of Bridges to
Our hypothetical patient is an individual
who makes less than $25,000 a year and, thus,
qualifies for Bridges to Access and who also uses
four albuterol inhalers. To make this calculation,
we compared the current average wholesale price of
Ventolin HFA to the mean of the average wholesale
prices for the three top selling generic albuterol
Average wholesale price, or AWP, is
commonly used as a pricing reference point for
distributors and payers in the healthcare system
and is calculated and reported by commercial data
GSK does not set an AWP for its products
or sell its products according to AWP and we
recognize published AWPs are different from actual
prices paid in the marketplace.
Based on the AWP comparison, the current
difference in price between Ventolin HFA and
generic albuterol is $9.49. Therefore, in our
example, if the patient did not enroll in Bridges
to Access, the extra cost per month would be $3.16
or $37.96 a year.
With assistance from Bridges to Access,
the cost of Ventolin HFA would be limited to a
one-time charge of $10.00 for the patient's first
60-day retail pharmacy fill. The patient would
then experience no added cost for further
prescription. In fact, the medicine would be
entirely free from that time forward.
Keep in mind that this hypothetical
patient, if not enrolled in Bridges to Access prior
to the transition, would previously have been
paying out of pocket for that generic albuterol.
For seniors or disabled persons, in
addition to Bridges to Access, GSK offers
saving programs, Orange Card and Together Rx to
help make GSK medicines more affordable. The GSK
Orange Card was the first of its kind. It is
available for Medicare beneficiaries without any
prescription-drug insurance and incomes of up to
$30,000 for an individual and up to $40,000 for a
Orange Card offers savings on GSK products
including Ventolin HFA to eligible Medicare
beneficiaries of up to 40 percent depending on a
pharmacy's usual and customary price for the
medicine. The program, Together Rx, is a
multi-company savings program and, as such,
provides access to a larger number of medicines.
This program was modeled after the GSK Orange Card
and has similar eligibility criteria.
Although the arrival of a Medicare drug
benefit in January 2006 should substantially lessen
the need for assistance of this kind, GSK's
commitment to helping patients access our medicines
In addition, GSK has committed
at least 2 million professional samples of Ventolin
HFA each year beginning a transition. Although
samples are distributed to physicians with no
conditions attached, we understand, anecdotally,
that many physicians do take medication-access
considerations into account in allocating samples
among their patients. Furthermore, GSK has
committed to freeze the price of Ventolin HFA from
November 5, 2003 until December 31, 2007.
In summary, GSK is committed to and has
global experience in transition to ozone-friendly
formulations. GSK has currently installed
production capacity to produce 15 million Ventolin
HFA MDIs per year. We are prepared to expand the
total capacity to approximately 30 million MDIs per
GSK has demonstrated an abiding commitment
to helping patients gain access to our medicines
and, towards this end, has patient-assistance
programs in place to help ensure access to Ventolin
HFA at transition. Finally, GSK has committed to
provide professional samples and freeze
of Ventolin HFA.
We expect that the criteria for
transition, as outlined in the 2002 Final Rule,
will be met with the support of all currently
approved albuterol HFA suppliers. Therefore, GSK
supports a transition date of December 31, 2005
which would allow for a smooth and orderly
transition for patients.
I would like to conclude by, once again,
thanking the advisory committee and the agency for
allowing GlaxoSmithKline the opportunity to present
DR. CHINCHILLI: Thank you, Dr. Jones.
Let's have our third speaker for this
DR. GARUTTI: Members of the committee,
Food and Drug Administration, invited guests,
ladies and gentlemen, good morning. My name is Dr.
Ron Garutti. I am a pediatrician and I am Group
Vice President of Global Regulatory Affairs at
Schering-Plough Research Institute.
On behalf of Schering-Plough Corporation,
I want to thank the FDA for the opportunity to
address the advisory committee today.
Let me say, at the outset, that our
company firmly supports the principles of the
January 29, 2003 petition of the U.S. Stakeholders,
which you have heard about, which requests an end
to the exemption for albuterol CFC-based in
inhalers. As pointed out, this exemption, after
all, was never intended to be permanent.
Now, I will not devote any of my
discussion today to the rationale for removing CFCs
from albuterol inhalers as I believe that that
rationale is well understood and accepted by most
interested parties as the right and necessary thing
In so removing CFCs, the United States
would be accomplishing the transition to a non-CFC
environment that has already successfully been
implemented by most of the European Union, Canada,
Australia, Japan and other countries.
So the important question,
for the committee is not if the transition should
be done but when. It can be done as soon as FDA,
in conjunction with the healthcare community and
the industry, is prepared to initiate the
It has been pointed out that in July,
2002, the FDA issued a final rule which set forth
the conditions that would have to be met before an
essential-use designation for albuterol inhalers
could be removed. Both Drs. Meyer and Sullivan
have noted them. Schering believes that all of the
necessary elements to remove the essential-use
designation can be met as early as December 31,
We acknowledge the proposed rule
distributed today and we are pleased to learn that
FDA plans to publish this on June 16. We are
hopeful that today's discussion will lead to the
establishment of a firm date.
As a company with more than twenty years
of respiratory experience and the first with our
partner 3M to introduce an HFA inhaler to
United States, Schering understands that we, in
conjunction with all of you and other members of
the professional asthma community, will be asking
millions of patients to change their behavior.
We recognize the significance of this
transition to patients and providers alike and we
are sensitive to the fact that ongoing
communication efforts will be essential elements to
ensuring that the transition is smooth and
To accomplish this effectively, however,
it is critical that FDA establish a clear timeline
to end the exemption because we believe that only
in doing so will there be the necessary stimulus to
drive the kind of provider and patient-behavior
change that will be required. Schering's
contribution, as well as that of others, to
effecting a successful transition hinges on
implementing the various elements of the transition
at the right time in relation to the effective
In the absence of such a date,
it will be
difficult to manage these various aspects
efficiently. For example, patients may not be
receptive to targeted communication efforts until a
fixed date has been established. It has been
pointed out, in addition, that significant planning
decisions and resource commitments required to
increase current production capacity need to be
made and, for us, we need about eighteen months in
advance of a known effective date.
That being said, Schering is poised to
play a part in a planned orderly transition and we
could be ready for an HFA-only environment as early
as the end of next year. We believe that for the
FDA to remove the exemption, certain assurances are
required. These are that safe and effective
alternatives are available, that patients and
providers are knowledgeable about and comfortable
with the use of the inhalers and that industry can
adequately meet the demand.
In the next few minutes, I will point out
that we do have safe and effective alternatives
right now and Schering will have
programs ready so that patients and providers will
be knowledgeable about and comfortable with their
HFA alternatives and that we can have an adequate
supply and production capacity of Proventil HFA
available again as early as December 31, 2005 or
within eighteen months of an established transition
Now, regarding the safe and effective
alternatives, following the issuance of the
Montreal Protocol in 1987 and after years of
research and development, Schering was the first
company to market, in collaboration with our
partner 3M, a non-CFC inhaler in the United States
Industry researchers had created HFAs that
were more environmentally friendly than CFCs.
These HFAs were then extensively tested to ensure
that they possessed the desired characteristics of
an MDI propellent. A wide range of toxicology
studies, comparable in scope to that for a new
molecular entity and consisting of acute, chronic
reproductive genetic and carcinogenicity
evaluations, established that certain HFA molecules
were, in fact, suitable candidates to replace CFCs
in inhaled delivery systems.
The new technology was then applied to
Proventil and, after a comprehensive clinical
program established that Proventil HFA was both
safe and effective, the FDA approved the product
for marketing clearance in 1996. In addition to
the clinical studies that were included in the NDA,
3M also conducted a robust observational
postmarketing program which studied more than 6,000
In the nearly eight years of postmarketing
patient experience to date, more than 17 million
prescriptions for Proventil HFA have been written.
Spontaneously reported adverse events, as you have
heard, have been consistent with the product's
labeling and similar in nature to that of its CFC
Taken together, available data clearly
support the established safety profile of Proventil
HFA and so, yes, we do have safe and
non-CFC alternatives available right now and, in
fact, with Glaxo's HFA product, there are, as said,
two such products available.
Let's turn now to another assurance
required before removing the exemption, that
relating to education and communication. Schering
is committed to playing its part in communicating
important information around the transition to both
patients and providers. Including in that
important information is reiteration of the message
that HFA inhalers are as safe and effective as the
CFC inhalers to which most patients are accustomed.
The HFA inhalers are also similar in size and shape
and as convenient to use.
Now, we all recognize, especially those
who treat asthma patients, that there can be a
significant psychological and emotional component
to asthma and its treatment. Asthma patients come
to rely on their inhalers and expect a certain type
of experience in using them. They tend to
associate activity of the drug and subsequent
relief with the forceful sensation of the
from a CFC inhaler has on the back of the throat.
I would point out that, with an HFA
inhaler, however, there is a softer spray and less
sensation although, of course, the active drug is
still effectively delivered to the lung. This fact
must this communicated to patients to ensure the
appropriate use of the product. Patients will also
need to be comfortable with the fact the drug from
an HFA inhaler may taste and smell slightly
different than that from a CFC inhaler.
Schering has always had educational
programs in support of our respiratory-care
business and messages such as those I have just
noted will be included in our developing multipoint
communication and awareness programs intended to
facilitate a safe and orderly transition.
Educational information will be accessible
via many channels including informational websites,
written materials available in physician's offices
and through our professional sales representatives.
Schering has traditionally had strong collaborative
working relationships with relevant
medical associations including both the American
Academy and the American College of Allergy, Asthma
and Immunology, the Academy of Family of
Physicians. We will continue to work with these
associations and others to develop appropriate
educational materials for patients and providers.
We especially appreciate the efforts of
organizations such as the allergy and asthma
network Mothers of Asthmatics in their own
commitments to educating and supporting the needs
of asthma patients.
Schering is also one of the founding
sponsors of the National Patient Safety Foundation
and has held a seat on its board of directors since
1997. This group is dedicated to improving patient
safety through educational programs and initiatives
and Schering will continue to provide input and
leadership on issues related to safe medication
As I stated in my introduction, the impact
of an expanded successful patient and provider
education campaign will be highly dependent
implementing the various elements at the right time
in relation to a proposed effective date. These
programs, to be maximally effective, will need to
be timed in coordination with the transition date
established by FDA so that the asthma community can
be optimally prepared.
On other point related to the transition,
it is, unfortunately, a fact and well known that
many asthma patients do not regularly visit their
healthcare provider. Schering believes, in
agreement with the U.S. Stakeholders, that the
transition will offer a good opportunity for
physicians and patients to increase their general
dialogue about asthma management.
A visit to the healthcare provider,
prompted by the switch to an HFA inhaler, will
allow for a reassessment of the patient's condition
and adjustment of treatment if deemed appropriate.
It will be especially useful for those patients who
may not have seen a physician for some time.
A third assurance required before removing
the exemption is that an adequate supply
production capacity of the HFA alternative will
exist. FDA has stated, and you have heard several
times today, that over 50 million albuterol
canisters are sold or distributed in the U.S. each
year. Schering currently supplies approximately
30 million units annually.
Our manufacturing partner, 3M, stands
ready to expand production in its facilities to
manufacture this amount of Proventil HFA and
Schering and 3M both have confidence that the
necessary capacity can be in place to meet our
share of the expected demand.
While much of the preparatory work to
expand capacity is well underway, advanced planning
activities and significant resource commitments
necessary to formally initiate this process require
some assurance of the timing of the transition.
The overall lead time to execute these steps,
including scale-up to current market demand, is
approximately eighteen months, again, thus, making
a fixed transition date established by FDA critical
for us and our partner.
In conclusion, the time to set a
transition date is now. Schering is confident that
we can meet our share of the demand and ensure that
asthma patients who need Proventil HFA are
adequately served. The focus throughout the
transition from CFC to HFA inhalers must be on
education and communication efforts towards
patients and providers. Schering is committed to
playing its part in effecting a successful
transition and supports the removal of the CFC
The first step requires that a proposed
final rule be published and a clear date
communicated so that all asthma stakeholders can
act together. Finally, Schering believes the U.S.
can join the group of countries who have already
undergone a successful removal of the exemption
because we do have safe and effective FDA
alternatives now. We will be educating patients
and providers and ensure their comfort level with
the transition and industry can adequately meet the
supply and demand.
DR. CHINCHILLI: Thank you, Dr. Garutti.
Do the committee members have any questions of our
three open presenters this morning? Dr. Schatz?
DR. SCHATZ: I guess a question for the
stakeholders. The presentation talked, actually,
about two aspects of concern. One was CFC
availability, itself, and then, obviously, the
detrimental aspects. But I was trying to get some
sense as to what the relative concerns were and if,
in fact, if CFC availability were assured, would
that change the thinking in terms of a time line?
MS. WEXLER: If CFC availability was--
DR. SCHATZ: A fair amount has been
emphasized about the concern as to whether CFCs
will continue to be available in terms of the
production as a rationale for the December 2005
date. My question was to what extent that one
factor is important and if CFC availability were
assured, if the production were not an issue, would
that affect your thinking in terms of a transition
MS. WEXLER: No. I think that they work
together to signal that these chemicals are being
eliminated. There is a reason that Honeywell has
been asked to shut the manufacturing plant in the
Netherlands and that is because the Dutch
government does not want CFCs produced on its soil.
It is a political statement about getting out of
To answer your question specifically, if
Baton Rouge were able to produce, it is not clear
that the international community would continue to
authorize those quantities and that would put the
stakeholders in the position of suggesting that we
don't care about international commitments.
The U.S., the government, has made a
commitment to comply with the Montreal Protocol and
so producing in Baton Rouge is only part of the
equation. It is that gets us the potential to use
them. But the right to use them legally needs to
be granted by the parties to the protocol. So they
have to work together in order for us to be able to
I think what, in some ways, you are asking
is would we support renouncing the protocol?
DR. SCHATZ: No. It is a matter of would
the date, would your date, change. I was trying to
get the sensitivity of your position to CFC
availability versus other considerations relative
to the date you suggest.
MS. WEXLER: Again, I think that they work
together. Given what we know about the timeline,
the U.S.--forgive me; I want to make sure it is
clear. We ask to use CFCs, wherever we get them
from. Regardless of where they are produced, each
country must ask the international process sort of
at the beginning of the year. We just put in our
request and those requests are two years in
So the request that the U.S. recently
submitted was for 2006 quantities. That request
was not welcomed completely. It was suggested that
the U.S. might want to reconsider that nomination
in light of this rulemaking or the rule that is go
So even if supply weren't necessarily an
issue, I think that it would be foolish for us to
believe that the international community is going
to continue to provide authorization to use those
CFCs indefinitely. So we are talking about a
2005-2006 timeframe for getting out of this and not
worrying about either of those conditions, of CFC
supply or the international community not granting
I think that, as we have heard, the
process of transitioning, making sure that the
HFA-installed capacity is there, making sure we
don't do anything precipitous and have a problem
and then have no CFC production capability and the
stockpiles of the CFCs that are available sort of
suggest that we want to kind of look towards the
sooner rather than later so that we buy ourselves
In other words, I don't think the protocol
parties will look kindly at a nomination for 2007
or 2008 regardless of whether Baton Rouge actually
ends up coming on line in a legal way.
DR. CHINCHILLI: Thank you. Dr.
DR. ATKINSON: I sort of get the
impression that one of the big concerns among the
committee members and the FDA also is the
possibility that a small percentage of asthma
patients might be unable to purchase the HFA units
that they need. GSK has a program, or described a
program, that was going to assist with that. I
wanted to ask Dr. Garutti if Schering had any such
program and if they were considering creating one
if they don't have one now.
DR. GARUTTI: Let me say this is a patient
group and a provider group that we care very deeply
about. We are committed to the respiratory
business. We have been in it a long time and we
are going to do whatever is necessary to serve our
First and foremost there is to make sure
that there is Proventil HFA available when we do
transition to the HFA-only environment. Currently,
as I have pointed out, that will entail a
significant ramp-up and a significant expenditure
of cost to get there. And we are confident we will
In fact, Schering-Plough does have a
patient assistance program. It is called SP Cares.
We have had it since, I believe, the mid-1990s. It
has similar eligibility requirements to those of
Glaxo's program, not entirely the same but similar.
Last year along we provided free drug of our
primary-care products including Proventil HFA to
some 75,000 low-income uninsured patients.
Periodically, we review the elements of
this program and criteria and we are committed to
continuing this program.
DR. CHINCHILLI: Thank you. Dr. Moss; you
had a question?
DR. MOSS: I was going to ask something
along the same lines. Maybe the people from GSK
and Schering can talk about how they are going to
market those programs for the uninsured, if they
have any plans for how to make physicians aware of
MS. WEXLER: I wanted to point out that,
in anticipation of this move, the stakeholders, on
our website which is at inhalertransition.org, has
listed all of the patient-assistance programs and
has link to them so that our member organizations
can now start to disseminate that information. So
we also will work with the companies to promote
DR. JONES: Yes. Bridges to Access,
actually, at the moment, has 435,000 patients in
its program. We have done a lot and will endeavor
to meet and strive towards this end. We have put a
lot of programs in place in order to be able to
reach as many people as possible and we will
continue to have these outreach efforts in place to
allow physicians and their associates to actually
be aware of these programs.
But, as I say, we have 435,000 at the
moment in the Bridges to Access program.
DR. CHINCHILLI: Thank you. Dr. Garutti?
DR. GARUTTI: I am not sure there is much
more we can add. As we have indicated, we are
developing many aspects of our communication
program. This is one element of them, the
awareness of the SP Cares program and we are going
to be working with various organizations that we
mentioned to make sure that it is more widely
communicated now as we transfer to an HFA-only
DR. CHINCHILLI: Any other questions from
committee members? If not, we are going to break
for lunch. I'm sorry; Dr. Meyer. I didn't see
DR. MEYER: Sorry; not to delay lunch. I
did want to make a clarification on an issue that
was left open from Ms. Wexler's talk earlier about
how the CFC sources is handled by the FDA because I
think she left that as kind of an open question.
Without getting into the details of the
Baton Rouge situation, what I would say is that the
FDA does not approve a CFC source, per se. What we
have done is we set standards for the purity that
is acceptable for CFCs when used in metered-dose
It is the expectation that the sponsor
of a product that uses those CFCs will provide us
evidence, both from the manufacturer as well as
their own testing, that the CFCs meet those
specifications and, if they do, then, in fact, they
can be used in that product.
DR. CHINCHILLI: Thank you for the
clarification. Let me make sure nobody else has
anything. Okay. We will break for lunch. We plan